Angiotensin II receptor blocking 2,3,6 substituted quinazolinones

ABSTRACT

This disclosure describes novel 2, 3, 6 substituted quinazolinones having the formula: ##STR1## wherein X, R, and R 6  are described in the specification which have activity as angiotensin II (AII) antagonists.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to certain 2,3,6 substituted quinazolinonecompounds which have demonstrated activity as angiotensin II (AII)antagonists and are therefore useful in alleviating angiotensin inducedhypertension and for treating congestive heart failure.

SUMMARY OF THE INVENTION

According to the present invention, there are provided novel compoundsof Formula I which have angiotensin II antagonizing properties and areuseful as hypertensives: ##STR2## wherein: R is ##STR3## --CO₂ H or--NHSO₂ CF₃ ; X is lower alkyl of 3 to 5 carbon atoms;

R⁶ is: ##STR4## R¹ is H, lower alkyl of 1 to 4 carbon atoms (optionallysubstituted with --OR⁷, --CO₂ R⁷, --CN, --N(R⁷)(R¹³), phenyl,substituted phenyl (substitution selected from mono-lower alkyl of 1 to3 carbon atoms, trifluoromethyl, nitro, O-alkyl of 1 to 3 carbon atoms,F, Cl, or Br)), phenyl, substituted phenyl (substitution selected frommono-lower alkyl of 1 to 3 carbon atoms, trifluoromethyl, nitro, O-alkylof 1 to 3 carbon atoms, F, Cl, or Br), pyridine, thiophene, furan,--OR⁷, --CO₂ R⁷, --CN, --CON(R⁷)(R¹³), --CF₃, --SPh, --N(R⁷)(R¹³) or##STR5## R² is H, lower alkyl of 1 to 4 carbon atoms (optionallysubstituted with --OR⁷, --CO₂ R⁷, --CN, --N(R⁷)(R¹³), phenyl,substituted phenyl (substitution selected from mono-lower alkyl of 1 to3 carbon atoms, trifluoromethyl, nitro, O-alkyl of 1 to 3 carbon atoms,F, Cl, or Br)), phenyl, substituted phenyl (substitution selected frommono-lower alkyl of 1 to 3 carbon atoms, trifluoromethyl, nitro, O-alkylof 1 to 3 carbon atoms, F, Cl, or Br), pyridine, thiophene, furan, --CO₂R⁷, --CN, --CON(R⁷)(R¹³), or ##STR6## R³ is H, lower alkyl of 1 to 4carbon atoms, phenyl, substituted phenyl (substitution selected frommono-lower alkyl of 1 to 3 carbon atoms, trifluoromethyl, nitro, O-alkylof 1 to 3 carbon atoms, F, Cl, or Br), pyridine, thiophene or furan,--CO₂ R⁷, --CON(R⁷)(R¹³), --CN, --NO₂, or ##STR7## R⁴ is H, --CO₂ R⁷,--SO₂ R¹², lower alkyl of 1 to 4 carbon atoms, benzyl, substitutedbenzyl (substitution selected from mono-lower alkyl of 1 to 3 carbonatoms, trifluoromethyl, nitro, O-alkyl of 1 to 3 carbon atoms, F, Cl, orBr), phenyl, substituted phenyl (substitution selected from mono-loweralkyl of 1 to 3 carbon atoms, trifluoromethyl, nitro, O-alkyl of 1 to 3carbon atoms, F, Cl, or Br), --CON(R⁷)(R¹³), or ##STR8## R¹² is phenyl,substituted phenyl (substitution selected from mono-lower alkyl of 1 to3 carbon atoms, trifluoromethyl, nitro, O-alkyl of 1 to 3 carbon atoms,F, Cl, or Br);

R⁵ is H, lower alkyl of 1 to 4 carbon atoms;

R⁷ is H, lower alkyl of 1 to 4 carbon atoms;

R⁸ is H, lower alkyl of 1 to 4 carbon atoms, phenyl, substituted phenyl(substitution selected from mono-lower alkyl of 1 to 3 carbon atoms,trifluoromethyl, nitro, O-alkyl of 1 to 3 carbon atoms, F, Cl, or Br),--CO₂ R⁷, --CH₂ OH, --CN, --CON(R⁷)(R¹³), or ##STR9## R⁹ is H, loweralkyl of 1 to 4 carbon atoms, phenyl, substituted phenyl (substitutionselected from mono-lower alkyl of 1 to 3 carbon atoms, trifluoromethyl,nitro, O-alkyl of 1 to 3 carbon atoms, F, Cl, or Br);

R¹⁰ is H, lower alkyl of 1 to 4 carbon atoms (optionally substitutedwith --OR⁷, --CO₂ R⁷, --CN, --N(R⁷)(R¹³), phenyl, substituted phenyl(substitution selected from mono-lower alkyl of 1 to 3 carbon atoms,trifluoromethyl, nitro, O-alkyl of 1 to 3 carbon atoms, F, Cl, or Br)),phenyl, substituted phenyl (substitution selected from mono-lower alkylof 1 to 3 carbon atoms, trifluoromethyl, nitro, O-alkyl of 1 to 3 carbonatoms, F, Cl, or Br), pyridine, thiophene, furan, --OR⁷, --CO₂ R⁷, --CN,--CON(R⁷)(R¹³), --CF₃, or ##STR10## R¹³ is H, lower alkyl of 1 to 4carbon atoms; Q is --O--, --(CR¹¹ R¹⁴)_(n) --, or a single bond;

Q¹ is --O--, --(CR¹¹ R¹⁴)_(n) --, ##STR11## or a single bond; n is 1 to5;

A is --(CR¹¹ R¹⁴)_(m) --;

m is 2 to 5, provided that n+m is not greater than 6;

R¹¹ is H, lower alkyl to 1 to 4 carbon atoms (optionally substitutedwith --OR⁷, --CO₂ R⁷, --CN, --N(R⁷)(R¹³), phenyl, substituted phenyl(substitution selected from mono-lower alkyl of 1 to 3 carbon atoms,trifluoromethyl, nitro, O-alkyl of 1 to 3 carbon atoms, F, Cl, or Br)),phenyl, substituted phenyl (substitution selected from mono-lower alkylof 1 to 3 carbon atoms, trifluoromethyl, nitro, O-alkyl of 1 to 3 carbonatoms, F, Cl, or Br), pyridine, thiophene, furan, --OR7, --CO₂ R⁷, --CN,--CON(R⁷)(R¹³), --CF₃, or ##STR12## R¹⁴ is H, lower alkyl of 1 to 4carbon atoms (optionally substituted with --OR⁷, --CO₂ R⁷, --CN,--N(R⁷)(R¹³), phenyl, substituted phenyl (substitution selected frommono-lower alkyl of 1 to 3 carbon atoms, trifluoromethyl, nitro, O-alkylof 1 to 3 carbon atoms, F, Cl, or Br)), phenyl, substituted phenyl(substitution selected from mono-lower alkyl of 1 to 3 carbon atoms,trifluoromethyl, nitro, O-alkyl of 1 to 3 carbon atoms, F, Cl, or Br),pyridine, thiophene, furan, --OR⁷, --CO₂ R⁷, --CN, --CON(R⁷)(R¹³),--CF₃, or ##STR13## and the pharmaceutically acceptable salts thereof.

The present invention also provides novel intermediate compounds,methods for making the novel 2,3,6 substituted quinazolinone angiotensinII antagonizing compounds, methods for making the novel intermediates,methods of using the novel quinazolinone angiotensin II antagonizingcompounds to treat hypertension, congestive heart failure and toantagonize the effects of angiotensin II.

DETAILED DESCRIPTION OF THE INVENTION

The novel compounds of the present invention are prepared according tothe following reaction schemes.

Referring to Scheme I, the corresponding anthranilic acid 2 where R²⁰ isI, Br or CH₃, is heated to reflux in alkyl acid anhydride 3 wherein X islower alkyl of 3 to 5 carbon atoms to provide the4H-3,1-benzoxazin-4-ones 4 which are isolated by concentrating thereaction mixtures and used without further purification. When the4H-3,1-benzoxazin-4-ones 4 are refluxed in ethyl alcohol containingammonia, or ammonium hydroxide solution, the quinazolinone intermediates5 are obtained. ##STR14##

The quinazolinone intermediates 5 are modified according to thefollowing reaction schemes to obtain the novel quinazolinone AngiotensinII antagonist compounds of the present invention.

In Scheme II, 6-methylquinazolinone 6, as prepared by Scheme I, isbrominated with N-bromosuccinimide to give the bromomethyl compound 7.Hydrolysis of the bromide with aqueous potassium carbonate indimethylsulfoxide yields the primary alcohol 8. The alcohol 8 isoxidized with pyridinium dichromate in N,N-dimethylformamide to affordaldehyde 9. The aldehyde 9 is reacted with a variety of GrignardReagents R¹ MgBr or lithium reagents R¹ Li in tetrahydrofuran where R¹is hereinbefore defined provided, however, that for this reactionscheme, R¹ cannot contain --CO₂ R₇, --CON(R⁷)(R¹³) or ##STR15## nor canit be H, --OR⁷, --CN, --CF₃, --SPh, or --N(R⁷)(R¹³) to give the desiredsecondary alcohol 10. Alcohol 10 is oxidized with pyridinium dichromatein N,N-dimethylformamide to afford ketone 11. ##STR16##

In an alternate route to 9, as shown in Scheme III,2-alkylsubstituted-6-iodo-4(1H)-quinazolinone 12, prepared by Scheme Iis reacted via a palladium catalyzed formylation. Additionally, 12 isconverted to ester 13 by palladium (II) catalyzed coupling in thepresence of carbon monoxide and methanol. Reduction of 13 with lithiumaluminum hydride in tetrahydrofuran gives alcohol 8. Alcohol 8 isoxidized with pyridinium dichromate to yield aldehyde 9. ##STR17##

As shown in Scheme IV, the palladium (II) catalyzed coupling of(trimethylsilyl)acetylene with2-alkylsubstituted-6-iodo-4(1H)-quinazolinone 12 yields the acetylenicquinazolinone 14. Desilylation of the acetylene with sodium hydroxide inwater-methanol gives the terminal acetylene 15. Hydration of acetylene15 with catalytic mercuric sulfate-sulfuric acid in acetic acid affordsmethyl ketone 16. The palladium (II) catalyzed coupling of substitutedacetylenes where R² is as defined hereinabove with2-alkylsubstituted-6-iodo-4(1H)-quinazolinone 12 yields the acetylenicquinazolinone 17. Hydration of 17 with catalytic mercuricsulfate-sulfuric acid in acetic acid gives a mixture of ketones 18 and35. The ketones are separated by chromatography. ##STR18##

In addition as shown in Scheme V, acetylene 15 is hydrogenated over 5%palladium-barium sulfate in pyridine to give either the terminal olefin21 or the ethyl substituted quinazolinone 22. Olefin 21 is separatedfrom 22 by chromatography. Also, acetylene 17 is hydrogenated over 5%palladium-barium sulfate in pyridine to give olefin 23 and alkylsubstituted quinazolinone 24. Olefin 23 is separated from 24 bychromatography. Additionally, 12 is converted to 21 by reaction withvinyltin in the presence of tetrakis(triphenylphosphine)palladium.Terminal olefin 21 is reacted with osmium tetroxide and sodium periodateto give aldehyde 9. ##STR19##

As shown in Scheme VI, olefinated quinazolinones 28 are obtained throughWittig olefination or Wadsworth-Emmons olefination of the aldehyde orketone 11, wherein R¹ is hereinbefore defined, by reaction with 26 or 27in the presence of base wherein R² and R¹⁰ are as defined hereinabove.

As described in EP 0 497 150, biphenyl 37 is attached to quinazolinoneintermediate 28 by initially alkylating the quinazolinone with apara-substituted benzyl bromide and subsequently attaching a secondphenyl moiety containing a trityl protected tetrazole or a cyano via atransition metal catalyzed coupling at the para position of the firstphenyl ring. Quinazolinone intermediates 21 and 23 are similarlyreacted. Alternatively, the coupling of quinazolinone intermediate 28where X, R¹, R² and R¹⁰ are as defined hereinabove with biphenyl 37where R¹⁸ is a trityl protected tetrazole prepared by the methods of N.B. Mantlo et al., J. Med. Chem. 34, 2919-2922(1991) or cyano prepared bymethods outlined in D. J. Carini, J. Med. Chem. 34, 2525-2547 (1991) isillustrated in Scheme VI and gives coupled product 59 by dissolving 28and 37 in acetone or another suitable solvent such asN,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone,methanol, ethanol, t-butanol, tetrahydrofuran, dioxane ordimethylsulfoxide, in the presence of excess potassium carbonate oranother suitable base such as sodium carbonate, cesium carbonate, sodiumethoxide, lithium methoxide, lithium diisopropylamide, lithiumbis(trimethylsilyl)amide, sodium t-butoxide or potassium t-butoxide for2-48 hours, at 20°-600° C. The obtained alkylated quinazolinone 59 maybe purified by chromatography or used as is in further transformations.Quinazolinone intermediates 21 and 23 are similarly reacted. ##STR20##

Referring to Scheme VII, alkylated quinazolinone 40 where X and R¹⁸ areas defined hereinabove is formed from intermediates 12 and 37 via themethods described for Scheme VI. Alkylated quinazolinone 40 is convertedto the trifluoromethyl olefin 42 through palladium catalyzed couplingwith trifluoroisopropenylzinc reagent 41 (Jiang, B.; Xu, Y.; J. Org.Chem, 56, 7336 (1991)). Additionally, reaction of alkylatedquinazolinone 40 with thiophenyl vinyltin using the method of magnus inJ. Chem. Soc. Chem. Comm. 522(1977) in the presence of a palladiumcatalyst as described by Quayle in Tet. Lett. 33(3) 413, (1992) givesthe vinyl sulfide substituted quinazolinone 43. Alkylated quinazolinone40 wherein X and R¹⁸ are as defined hereinabove is converted to 84 byreaction of 40 with 83, wherein R², R⁷ and R¹⁰ are as definedhereinabove provided, however, that for this reaction scheme R⁷ cannotbe H, in the presence of tetra-kis-triphenylphosphine palladium(0) andtoluene. Reagent 83 is formed from 82 wherein R², R⁷ and R¹⁰ are asdefined hereinabove provided, however, that for this reaction scheme R⁷cannot be H by reaction with n-BuLi followed by Bu₃ SnCl. Intermediate82, wherein R², R⁷ and R¹⁰ are as defined hereinabove provided, however,that for this recreation scheme R⁷ cannot be H, is obtained from 81 bythe method described in "Advanced Organic Chemistry," March, pp 346,789, 925.

Scheme VIII describes an alternate route to trifluoromethyl olefin 42.Quinazolinone 9 where X is hereinbefore defined is coupled with biphenyl37 where R¹⁸ is hereinbefore defined, using the methods shown in SchemeVII to give alkylated quinazolinone 44. Reaction of alkylatedquinazolinone 44 with trifluoromethyl iodide and zinc inN,N-dimethylformamide gives alcohol 45. Alcohol 45 is oxidized with1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one 46 using themethod of R. J. Linderman and D. M. Graves, Tet. Lett., 28(37)4259(1987) to afford ketone 47. Olefin 42 is formed by a Wittig reactionon ketone 47 with Wittig reagent Ph₃ P═CH₂.

Referring to Scheme IX, quinazolinone 16 where X is hereinbefore definedis coupled with biphenyl 37 where R¹⁸ is hereinbefore defined, using themethods shown in scheme VII, to give alkylated quinazolinone 48.Reaction of alkylated quinazolinone 48 with trimethylsilyl cyanide inthe presence of zinc iodide (oda, M.; Yamamuro, A.; Watabe, T., Chem.Lett, 1427 (1979)) gives the trimethylsilyl- cyanohydrin 49 where R¹⁸ isthe free tetrazole which is further reacted with phosphorous oxychlorideor other suitable dehydrating agent, such as KHSO₄, H₂ SO₄, BF₃ --OEt₂,acetic anhydride/pyridine to give the cyano substituted olefin 50.

Alkylated quinazolinone 48 wherein X and R¹⁸ are hereinbefore defined isreacted with amine HN(R⁷)(R¹³), where R⁷ and R¹³ are as definedhereinabove provided, however, that for this reaction scheme neither R⁷nor R¹³ may be H, with removal of water to give 80. ##STR21##

As shovn in Scheme X, alkylated quinazolinone 48 is reacted with aqueoussodium hydroxide in the presence of chloroform andbenzyltrimethylammonium chloride to give carboxylic acid 51.Additionally, carboxylic acid 51 is reacted with methyl alcohol in thepresence of 4-dimethylaminopyridine and dicyclohexylcarbodiimide toafford methyl ester 52.

As shown in Scheme XI, olefin 54 is prepared by the addition of aGrignard reagent R¹ MgBr, to 48 where R¹ is hereinbefore definedprovided, however, that for this reaction scheme R¹ cannot contain --CO₂R⁷, --CON(R⁷)(R¹³) or ##STR22## nor can it be H, --OR⁷, --CN, --CF₃,--SPh, or --N(R⁷)(R¹³) to provide alcohol 53. The alcohol is dehydratedwith {bis[α,α-bis(trifluoromethyl)benzenemethanolato]diphenylsulfur} orwith sulfuric, hydrochloric, or p-toluenesulfonic acid to give olefin54. ##STR23##

The synthesis of α,β-unsaturated esters and amides is illustrated inScheme XII. Quinazolinone 48 is reacted with enol triflates (Scott, W.J., McMurry, J. E., Accounts of Chemical Research 21(2), 47(1988)) toafford 55. Palladium catalyzed coupling of 55 (Cacchi, S.; Morera, e.;Ortar, G., Tet. Letters, 26(8), 1109(1985)) with alcohol R⁵ OH, where R⁵is hereinbefore defined provided, however, that for this reaction schemeR⁵ cannot be H gives ester 56. Palladium catalyzed coupling of 55 withamine HN(R⁷)(R¹³) where R⁷ and R¹³ are hereinbefore defined gives amide57. ##STR24##

As outlined in Scheme XIII, alkylated quinazolinone 61, where R¹, R²,R¹⁰ , R¹⁸ and X are hereinbefore defined is reacted with nitrone 61prepared from 60 wherein R⁸ , Q and A are hereinbefore defined and R³⁰is H, by using the hydrogen peroxide-selenium dioxide method of S-I.Murahashi and T. Shiota, Tet. Letters, 28(21) 2383(1987) or by oxidationwith mercuric oxide in chloroform when R 30 is OH to give bicyclicderivative 62. Quinazolinones 42, 43, 50, 52, 54, 56, 57, 80 and 84 aresimilarly reacted.

Deprotection of the trityl group is accomplished by refluxing an aqueousacetone solution of the alkylated quinazolinone 62 with a catalyticamount of hydrochloric acid or other suitable acid such as sulfuric,trifluoroacetic or hydrogen chloride for 2-24 hours. Additionally,heating 62 in tetrahydrofuran-methanol removes the trityl protectinggroup and affords 63. Reaction of 62 where R¹⁸ is cyano with sodiumazide in the presence of tri-n-butyltin chloride in refluxing xyleneaffords the desired tetrazole 63. Contemplated equivalents totri-n-butyltin chloride include tri-(lower alkyl C₁ -C₄)Tin chloridesand bromides. Contemplated equivalents to sodium azide include potassiumazide and lithium azide.

Heating 62 where R¹⁸ is a trityl protected tetrazole, with zinc inacetic acid affords amino alcohol 66. Alternatively, heating 63 withzinc in acetic acid also gives amino alcohol 66. ##STR25##

As shown in Scheme XIV, alkylated quinazolinone 59, where R¹, R², R¹⁰ ,R¹⁸ and X are hereinbefore defined is reacted with nitrone 67, preparedfrom 68 where R³ and R⁸ are hereinbefore defined and R³⁰ is H, by usingthe hydrogen peroxide-selenium dioxide method of S-I. Murahashi and T.Shiota, Tet. Letters, 28(21) 2383(1987) to give tricyclic derivative 69.Quinazolinones 42, 43, 50, 52, 54, 56, 57, 80 and 84 are similarlyreacted. Deprotection of the trityl group is accomplished by refluxingan aqueous acetone solution of the alkylated quinazolinone 69 with acatalytic amount of hydrochloric acid or other suitable acid such assulfuric, trifluoroacetic or hydrogen chloride for 2-24 hours.Additionally, heating 69 in tetrahydrofuran-methanol removes the tritylprotecting group and affords 70. Reaction of 69 where R¹⁸ is cyano withsodium azide in the presence of tri-n-butyltin chloride in refluxingxylene affords the desired tetrazole 70. Contemplated equivalents totri-n-butyltin chloride include tri-(lower alkyl C₁ -C₄ tin chloridesand bromides. Contemplated equivalents to sodium azide include potassiumazide and lithium azide.

Heating 69 where R¹⁸ is a trityl protected tetrazole, with zinc inacetic acid affords amino alcohol 71. Alternatively, heating 70 withzinc in acetic acid also gives amino alcohol 71. ##STR26##

Referring to scheme XV, ketone 11 wherein R¹ and X are hereinbeforedefined is coupled to biphenyl 37 where R¹⁸ is hereinbefore defined,using the coupling method shown in scheme VII to give alkylatedquinazolinone 58. Quinazolinones 9, 16 and 18 are similarly reacted.olefin 74 wherein R¹ and R² are as defined hereinabove may be preparedfrom ketone 58 via Witting reaction with a substituted phosphorane whichis prepared by known methods. Olefin 74 is oxidized with pyridiniumdichloromate to give carbonyl 75 wherein R¹, R², R⁹, A and Q¹ and asdefined hereinabove.

Alternatively, alkylated quinazolinone 40 where X and R¹⁸ arehereinbefore defined, is reacted with acetylene 72, where Q¹ and A arehereinbefore defined, in the presence of a palladium(II) catalyst togive alcohol 73. Hydrogenation of 73 gives olefin 74 which is oxidizedwith pyridinium dichromate to give carbonyl 75. Reaction of carbonyl 75with oxime R⁴ NHOH 76 where R⁴ is hereinbefore defined affords thenitrone 77 which cyclizes to give bicyclic derivatives 78.

Deprotection of the trityl group is accomplished by refluxing an aqueousacetone solution of the alkylated quinazolinone 78 with a catalyticamount of hydrochloric acid or other suitable acid such as sulfuric,trifluoroacetic or hydrogen chloride for 2-24 hours. Additionally,heating 78 in tetrahydrofuran-methanol removes the trityl protectinggroup and affords 79. Reaction of 78 where R¹⁸ is cyano with sodiumazide in the presence of tri-n-butyltin chloride in refluxing xyleneaffords the desired tetrazole 79. Contemplated equivalents totri-n-butyltin chloride iclude tri-(lower alkyl C₁ -C₄)Tin chlorides andbromides. Contemplated equivalents to sodium azide include potassiumazide and lithium azide.

Additionally, heating 78 where R¹⁸ is a trityl protected tetrazole, withzinc in acetic acid affords amino alcohol 90. Alternatively, heating 79with zinc in acetic acid also gives amino alcohol 90.

Reactions are performed in a solvent appropriate to the reagents andmaterials employed and suitable for the transformation,being effected.It is understood by those skilled in the art of organic synthesis thatthe various functionalities present on the molecule must be consistentwith the chemical transformations proposed. This may necessitatejudgement as to the order of synthetic steps, protecting groups, ifrequired, and deprotection conditions. Substituents on the startingmaterials may be incompatible with some of the reaction conditions. Suchrestrictions to the substituents which are compatible with the reactionconditions will be apparent to one skilled in the art.

Pharmaceutically suitable salts include both the metallic (inorganic)salts and organic salts; a list of which is given in Remington'sPharmaceutical Sciences, 17th Edition, pg. 1418 (1985). It is well knownto one skilled in the art that an appropriate salt form is chosen basedon physical and chemical stability, flowability, hydroseopicity andsolubility. Preferred salts of this invention for the reasons citedabove include potassium, sodium, calcium, magnesium and ammonium salts.

Some of the compounds of the hereinbefore described schemes have centersof asymmetry. The compounds may, therefore, exist in at least two andoften more stereoisomeric forms. The present invention encompasses allstereoisomers of the compounds whether free from other stereoisomers oradmixed with other stereoisomers in any proportion and thus includes,for instance, racemic mixture of enantiomers as well as thediastereomeric mixture of isomers.. The absolute configuration of anycompound may be determined by conventional X-ray crystallography.

While the invention has been illustrated using the trityl protectinggroup on the tetrazole, it will be apparent to those skilled in the artthat other nitrogen protecting groups may be utilized. Contemplatedequivalent protecting groups include, benzyl, p-nitrobenzyl,propionitrile or any other protecting group suitable for protecting thetetrazole nitrogen. Additionally, it will be apparent to those skilledin the art that removal of the various nitrogen protecting groups, otherthan trityl, may require methods other than dilute acid.

The compounds of this invention and their preparation are illustrated bythe following non-limiting examples.

EXAMPLE 1 2-Butyl-6-(methyl)-4(1H)-quinazolinone

To 20.0 g of 2-amino-5-methylbenzoic acid is added 60 ml of valericanhydride. The mixture is heated at reflux for 18 hours and thenconcentrated under reduced pressure. The resulting brown solid residueis dissolved in a mixture of 200 ml of 30% of ammonium hydroxidesolution and 300 ml of ethyl alcohol. This mixture is heated at refluxfor 5 hours and then allowed to cool to room temperature. After cooling,the precipitate is collected by filtration. The cake is washed withethanol and water, then dried under vacuum to give 8.92 g of thequinazolinone as a white solid. CI MASS SPEC MH⁺ =217.

EXAMPLE 2 2-Butyl-6-iodo-4(1H)-quinazolinone

The method of Example 1 is used with 2-amino-5-iodobenzoic acid toprepare the desired product, m.p. 257°-258° C.

EXAMPLE 3 2-Butyl-6-(bromomethyl)-4(1H)-quinazolinone

To a suspension of 3.50 g of 6-methylquinazolone in 100 ml of chloroformis added 3.39 g of N-bromosuccinimide and 0.25 g of benzoyl peroxide.The reaction mixture is heated at reflux for 18 hours and then filteredhot. A precipitate of 2.21 g of an inseparable mixture of the desiredbromide and starting 6-methyl-quinazolinone is obtained and used inExample 4 without further purification.

EXAMPLE 4 2-Butyl-6-(hydroxymethyl)-4(1H)-quinazolinone

To a suspension of 2.0 g of impure2-butyl-6-(bromomethyl)-4(1H)-quinazolinone (from Example 3) in 35 ml ofdimethylsulfoxide and 20 ml of water is added 1.0 g of potassiumcarbonate. The reaction mixture is heated at reflux for 6 hours,resulting in a complete solution. Upon cooling slowly to roomtemperature a white precipitate forms and is collected by filtration.The filter cake is purified by flash chromatography on silica gel,eluting with 9:1 chloroform-methanol to give 0.67 g of the desiredproduct as a white solid. CI MASS SPEC 233(M+H).

EXAMPLE 5 2-Butyl-1,4- dihydro-4-oxo-6-quinazolinecarboxaldehyde

To a solution of 0.3 g of 2-butyl-6-(hydroxymethyl)-4(1H)-quinazolinonein 3.5 ml of dry N,N-dimethylformamide is added 1.7 g of pyridiniumdichromate. The reaction mixture is stirred at room temperature for 16hours and then poured into 125 ml of water. The resulting precipitate isremoved by filtration and the filtrate extracted with 9:1chloroformmethanol. The combined organic extracts are dried overmagnesium sulfate, filtered and concentrated in vacuo and combined withthe precipitate above. The combined solids are purified by flashchromatography on silica gel by eluting with 1:1 ethyl acetate-hexanesto give 0.27 g of the desired product. CI MASS SPEC 231(M+H).

EXAMPLE 6 2-Butyl-6-(1-hydroxyethyl)-4(1H)-quinazolinone

To a solution of 0.60 g of2-butyl-1,4-dihydro-4-oxo-6-quinazolinecarboxaldehyde in 30 ml of drytetrahydrofuran, cooled to 0° C. is added dropwise, 2.61 ml of a 3.0Msolution of methylmagnesium bromide in diethyl ether. The reaction isstirred at 0° C. for 30 minutes and then quenched with 10 ml of aqueousammonium chloride. After diluting with 10 ml of water, the reactionmixture is extracted with 9:1 chloroformmethanol. The combined extractsare dried with magnesium sulfate, filtered and concentrated to yield0.64 g of the desired product.

CI MASS SPEC 247(Mh⁺).

EXAMPLE 7 2-Butyl-6-(1-hydroxypropyl)-4(1H)-quinazolinone

To a solution of 0.25 g of2-butyl-1,4-dihydro-4-oxo-6-quinazolinecarboxaldehyde in 10 ml of drytetrahydrofuran, cooled to 0° C., is added 1.63 ml of 2.0M ethylmagnesium bromide in tetrahydrofuran. The reaction mixture is stirredfor 30 minutes at 0° and quenched with 20 ml of saturated ammoniumchloride solution and 20 ml of water. The reaction mixture is extractedwith 9:1 chloroform-methanol, dried over magnesium sulfate, filtered andevaporated in vacuo to give 0.26 g of the desired product.

CI MASS SPEC 261(MH⁺).

EXAMPLE 8 2-Butyl-1,4-dihydro-4-oxo-6-quinazoline-carboxaldehyde

To a solution of 1.0 g of 2-butyl-6-iodo-4(1H)-quinazolinone and 0.355 gof tetrakis(triphenylphosphine)palladium in 15 ml of tetrahydrofuran and5 ml of N,N-dimethylformamide, heated to 55° C. under an atmosphere ofcarbon monoxide is added a solution of 1.40 g of tri-n-butyltin hydridein 2.5 ml of toluene over 6 hours via a syringe pump. After the additionis complete the reaction is allowed to cool to room temperature, dilutedwith brine and extracted with chloroform. The combined organics areconcentrated in vacuo and the resulting residue triturated with ether.The precipitate is collected by filtration and purified by flashchromatography on silica gel, eluting with 1:1 ethyl acetate-hexanes togive 0.35 g of the desired product, m.p. 242°-244° C.

EXAMPLE 9 2-Butyl-6-[(trimethylsilyl)ethylnyl]-4(1H)-quinazolinone

To a solution of 1.0 g of 2-butyl-6-iodo-4(1H)-quinazolinone 0.043 g ofbis(triphenylphosphine) palladium (II) chloride and 5.8 mg of copper (I)iodide in 5.0 ml of N,N-dimethylformamide and 5.0 ml of triethylamine isadded 0.36 g of (trimethylsilyl)acetylene. The resulting reactionmixture is heated at 45° C. for 1 hour and then 65° C. for 5 hours. Uponcooling, the reaction mixture is concentrated in vacuo and the residuepurified by flash chromatography on silica gel, eluting with 1:3 ethylacetate-hexane to yield 0.75 g of the desired product as a white solid.CI MASS SPEC 299(MH⁺).

EXAMPLE 10 2-Butyl-6-ethylnyl-4(1H)-quinazolinone

To a solution of 0.70 g of2-butyl-6-[(trimethylsilyl)ethynyl]-4(1H)-quinazolinone in 20 ml ofmethanol and 20 ml of tetrahydrofuran is added 10.0 ml of 1.0 N sodiumhydroxide solution. The reaction is stirred at room temperature for 2hours and then diluted with 5% hydrochloric acid solution until the pHis 2. The resulting tan precipitate is collected by filtration and driedin vacuo to yield 0.50 g of the desired product. CI MASS SPEC 227(MH⁺).

EXAMPLE 11 6-Acetyl-2-butyl-4(1H)-quinazolinone

To a solution of 1.20 of 2-butyl-6-ethynyl-4(1H)-quinazolinone in 90 mlof acetic acid is added 0.45 g of mercuric sulfate, 0.9 ml of water and0.3 ml of sulfuric acid. The reaction mixture is heated at reflux for 5hours, cooled to room temperature and quenched with 150 ml of water. Theresulting mixture is concentrated in vacuo, diluted with 150 ml of waterand extracted with 6:1 chloroform-reethanol. The combined organics aredried over magnesium sulfate, filtered and concentrated in vacuo. Theresidue is purified by flash chromatography on silica gel, eluting with1:1 ethyl acetate-hexanes to give 0.67 g of the desired product as awhite solid.

CI MASS SPEC 245(MH⁺).

EXAMPLE 12 2-Butyl-6-(1-hydroxy-1-methylethyl)-4(1H)-quinazolinone

To a solution of 4.00 g of 6-acetyl-2-butyl-4-(1H)-quinazolinone in 250ml of dry tetrahydrofuran, cooled to 0° C., is added dropwise 16.4 ml of3.0M methylmagnesium bromide in diethyl ether. The reaction is stirredat 0° C. for 0.5 hours and then allowed to warm to room temperaturefollowed by quenching with 100 ml of saturated ammonium chloridesolution. The mixture is diluted with 50 ml of water and extracted withethyl acetate. The combined organic layers are washed with brine, driedover anhydrous magnesium sulfate, filtered and concentrated in vacuo.The residue is purified by flash chromatography on silica gel, elutingwith 100:0.25 chloroform-reethanol to give 2.75 g of the desired productas a white solid.

CI MASS SPEC 261(MH⁺).

EXAMPLE 13 2-Butyl-6-(1-hydroxyethyl)-4(1H)-quinazolinone

To a suspension of 0.102 g of 6-acetyl-2-butyl-4(1H)-quinazolinone in10.0 ml of ethanol is added 0.015 g of sodium borohydride. The reactionmixture is stirred for 1.5 hours at room temperature and then dilutedwith 50 ml of water. The aqueous layer is extracted with 5:1chloroform-reethanol and the combined organics dried over magnesiumsulfate, filtered and concentrated in vacuo to yield 0.103 g of thedesired product.

CI MASS SPEC 247(MH⁺).

EXAMPLE 14 Methyl 2-butyl-1,4-dihydro-4-oxo-6-quinazolinecarboxylate

To a solution of 1.00 g of 2-butyl-6-iodo-4(1H)-quinazolinone and 6.0 mlof triethylamine in 25 ml of methanol and 5 ml of N,N-dimethylformamideis added 0.275 g of bis-(triphenylphosphine)palladium (II) chloride. Thereaction mixture is heated at reflux under an atmosphere of carbonmonoxide for 16 hours, then allowed to cool and concentrated in vacuo.The residue is purified by flash chromatography on silica gel, elutingwith 1:1 ethyl acetate-hexanes to give 0.389 g of the desired product asa white solid.

CI MASS SPEC 261(MH⁺).

EXAMPLE 15 2-Butyl-6-(1-hydroxy-1-methylethyl)-4(1H)-quinazolinone

To a solution of 0.075 g of methyl2-butyl-1,4-dihydro-4-oxo-6-quinazolinecarboxylate in 5 ml of drytetrahydrofuran, cooled to 0° C., is added dropwise 0.51 ml of asolution of 3.OM methylmagnesium bromide in diethyl ether. The reactionis stirred at 0° C. for 0.5 hours and then at room temperature for 1hour followed by quenching with 10 ml of saturated ammonium chloridesolution. The resulting reaction mixture is diluted with 10 ml of waterand extracted with ethyl acetate. The combined organics are dried overmagnesium sulfate, filtered and concentrated in vacuo. The residue ispurified by flash chromatography on silica gel, eluting with 100:0.25chloroform-reethanol to yield 0.055 g of the desired product as a whitesolid, m.p. 190°-192° C.

EXAMPLE 16 2-Butyl-6-(1-methylethenyl)-4(1H)-quinazolinone

To a suspension of 3.66 g of methyltriphenylphosphonium bromide in 30 mlof dry tetrahydrofuran, cooled to -78° C., is added dropwise 5.9 ml of a1.73M solution of n-butyllithium in hexanes. Following completeaddition, the reaction mixture is allowed to warm to room temperatureand stirred for 15 minutes, until all the phosphonium bromide isdissolved. The reaction mixture is then recooled to -78° C. and asuspension of 6-acetyl-2-butyl-4(1H)-quinazolinone in 15 ml of drytetrahydrofuran is added. The reaction is allowed to warm to roomtemperature and stirred for 24 hours followed by quenching withsaturated ammonium chloride solution. After diluting with 10 ml ofwater, the aqueous layer is extracted with chloroform and the combinedorganics dried over magnesium sulfate, filtered and concentrated invacuo. The residue is purified by flash chromatography on silica gel,eluting with 1:2 ethyl acetate-hexanes to give 0.23 g of the desiredproduct as a white solid.

CI MASS SPEC 243(MH⁺).

EXAMPLE 17 2-Butyl-6-(hydroxyphenylmethyl)-4(1H)-quinazolinone

To a stirred solution of 2.00 g of2-butyl-1,4-dihydro-4-oxo-6-quinazolinecarboxaldehyde in 100 ml oftetrahydrofuran, cooled at 0° C., is added 13.0 ml of 2.0 Mphenyllithium and stirring continued for 1 hour. The cooling is removedand the reaction allowed to reach room temperature followed by anadditional 30 minutes at room temperature. The reaction is diluted withsaturated ammonium chloride solution and extracted with ethyl acetate.The organic layer is dried, evaporated to a residue, which is purifiedby chromatography on silica gel by elution with 0.25:100methanol-chloroform to give 0.932 g of the desired product.

CI MASS SPEC 309(MH⁺).

EXAMPLE 18 2-Butyl-6-ethenyl-4(1H-)-quinazolinone

A mixture of 2.00 g of 2-butyl-6-ethylnyl-4(1H)-quinazolinone and 0.200g of 5% palladium-barium sulfate in 100 ml of pyridine is treated with 1atmosphere of hydrogen at room temperature until 225 ml of hydrogen isused. The reaction mixture is filtered through diatomaceous earth andthe cake washed with 100 ml of pyridine and 100 ml of methanol. Thecombined filtrates are evaporated to a residue which is purified bychromatography on silica gel using 1:2 ethyl acetate-hexanes to afford0.786 g of the desired product.

CI MASS SPEC 229 MH⁺).

EXAMPLE 19 2-Butyl-6-ethenyl-4(1H)-quinazolinone

A mixture of 12.28 g of 2-butyl-6-iodo-4(1H)-quinazolinone 0.866 g oftetrakis (triphenylphosphine)palladium, 0.015 g of 2,6-di-t-butyl-4-methylphenol in 75 ml of toluene and 20 ml ofN,N-dimethylformamide is treated with 13.06 g of tri-n-butyl vinyltinfollowed by heating at reflux for 4 hours. The reaction mixture iscooled and concentrated in vacuo. The residue is diluted with hexanesand filtered. The filter cake is washed with hexanes and the remainingtacky solid dissolved in 100 ml of chloroform-reethanol (8:2) andpurified by chromatography on silica gel with 1:3 ethyl acetate-hexanesto afford 4.55 g of the desired product as a yellow solid. CI MASS SPEC229MH⁺).

EXAMPLE 202-Butyl-6-iodo-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone

A mixture of 5.00 g of 2-butyl-6-iodo-4(1H)-quinazolinone, 16.98 g of5-[4'-(bromomethyl)[1,1'-bi-phenyl]-2-yl]-1-(triphenylmethyl)-1H-tetrazole and 0.695 g of lithium methoxide in 60 ml oftetrahydrofuran is heated at reflux for 40 hours. The reaction mixtureis cooled, filtered and concentrated in vacuo to a residue which ispurified by column chromatography on silica gel by elution with 1:9ethyl acetate-hexanes to 1:5 ethyl acetate-hexanes to give 6.638 g ofthe desired product as a solid. FAB MASS SPEC 805 (M+H)

EXAMPLE 216-Acetyl-2-butyl-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone

A suspension of 0.250 g of 6-acetyl-2-butyl-4(1H)-quinazolinone, 0.685 gof 5-[4'-(bromomethyl)-[1,1'-biphenyl]-2-yl]-1-(triphenylmethyl)-1H-tetrazole and 0.424 g of anhydrous potassium carbonate in 25.0 ml ofdry acetone is heated at reflux for 16 hours. The reaction mixture isalowed to cool to room temperature, filtered and the filtrate evaporatedin vacuo to a residue. The residue is purified by column chromatographyon silica gel using 1:3 ethyl acetate-hexanes to give 0.43 g of thedesired product as a solid, m.p. 104°-105° C.

EXAMPLE 22 2-Butyl-6-ethenyl-4(1H)-quinazolinone

To a suspension of 15.14 g of mothyltriphenylphosphonium bromide intetrahydrofuran, cooled to -78° C., is slowly added 21.73 ml of 1.95 Mn-butyllithium in hexanes. The reaction mixture is allowed to warm toroom temperature and stirred until all of the phosphonium saltdissolves. This takes approximately 30 minutes. The reaction mixture iscooled to -78° C. and 1.95 g of2-butyl-1,4-dihydro-4-oxo-6-quinazolinecarboxaldehyde added in oneportion as a solid. The reaction mixture is allowed to warm to roomtemperature and stirred for 18 hours. The reaction mixture is quenchedwith saturated ammonium chloride, diluted with water and extracted withethyl acetate. The organic layer is separated, washed with briner driedwith MgSO₄ and concentrated in vacuo to a residue which is purified bychromatography on silica gel using 1:3 ethyl acetate-hexanes to give2.48 g of the desired product as a solid. CI MASS SPEC 229 (M+H)

EXAMPLE 23 2-Butyl-6-(1-hydroxy-1-phenylethyl)-4(1H)-quinazolinone

To a solution of 2.08 g of 6-acetyl-2-butyl-4(1H)-quinazolinone in 80 mlof tetrahydrofuran is added dropwise at room temperature 14.2 ml of 3.0Mphenylmagnesium bromide. The reaction mixture is stirred at roomtemperature overnight then diluted with aqueous ammonium chloride andextracted with chloroform. The organic layer is dried and evaporated invacuo to a residue which is purified by column chromatography on silicagel by elution with 1:1 ethyl acetate-hexanes to give 0.535 g of thedesired product as a solid. Cl MASS SPEC 323 (MH⁺).

EXAMPLE 24 Ethyl3-(2-butyl-1,4-dihydro-4-oxo-6-quinazolinyl)-2-propenoate

A mixture of 3.202 g of2-butyl-1,4-dihydro-4-oxo-6-quinazolinecarboxaldehyde and 5.093 g of(carbethoxymethylene)triphenylphosphorane in 50 ml of acetonitrile isheated at reflux for 18 hours. The reaction mixture is cooled and theresulting solid washed with ether and dried to give 1.94 g of thedesired product. CI MASS SPEC 301 (MH⁺)

EXAMPLE 252-Butyl-6-ethenyl-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone

To a suspension of 4.49 g of 2-Butyl-6-ethenyl-4(1H)-quinazolinone in 70ml of dry tetrabydrofuran at room temperature is rapidly added 23.63 9of a 1.0M solution of lithium bis(trimethylsilyl)amide intetrahydrofuran. After stirring for 20 minutes at room temperature 21.94g of5-(4'-(bromomethyl)-[1,1'-biphenyl]-2-yl]-1-(triphenylmethyl)-1H-tetrazoleis rapidly added in one portion and the reaction mixture heated atreflux for 48 hours. After cooling to room temperature, the reactionmixture is concentrated in vacuo to a residue which is purified bychromatography on silica gel by eluting with 1:3 ethyl acetate-hexanesto give 9.58 g of the desired product as a yellow solid. FAB MASS SPEC705 (M+H)

EXAMPLE 262-Butyl-6-(1-hydroxy-1-phenylethyl)-3-[[-2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl[]1,1'-biphenyl]-4-yl]methyl-4(3H)-quinazolinone

To a suspension of 0.535 g of2-Butyl-6-(1-hydroxy-1-phenylethyl)-4(1H)-quinazolinone in 6.5 ml of drytetrahydrofuran at room temperature is rapidly added 1.99 ml of a 1.0Msolution of lithium bis(trimethylsilyl)amide in tetrahydrofuran. Afterstirring for 20 minutes at room temperature 1.851 g of5-(4'-(bromomethyl)-[1,1'-biphenyl]-2-yl]-1-(triphenylmethyl)-1H-tetrazoleis rapidly added in one portion and the reaction mixture heated atreflux for 48 hours. After cooling to room temperature, the reactionmixture is concentrated in vacuo to a residue which is purified bychromatography on silica gel by eluting with 1:3 ethyl acetate-hexanesto give 0.790 g of the desired product as a solid. FAB MASS SPEC 821(M+Na)

EXAMPLE 27 2-Butyl-6-(1-methylethenyl)-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl-4(3H)-quinazolinone

A mixture of 0.207 g of 2-butyl-6-(1-methylethenyl)-4(1H)-quinazolinone,0.571 g of 5-(4'-(bromomethyl)-[1,1'-biphenyl]-2-yl]-1-(triphenylmethyl)-1H-tetrazole and 0.354 g of potassium carbonate in 20.0 ml of acetoneis heated at reflux for 16 hours. The reaction mixture is cooled,filtered and the filtrate concentrated in vacuo to a residue which ispurified by column chromatography on silica gel with 1:6 ethylacetate-hexanes to give 0.220 g of the desired product as a solid. FABMASS SPEC 719 (M+H)

EXAMPLE 282-Butyl-6-(1-phenylethenyl-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]-methyl]-4(3H)-quinazolinone

A mixture of 0.760 g of2-Butyl-6-(1-hydroxy-1-phenylethyl)-3-[[-2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1-biphenyl]-4-yl]methyl-4(3H)-quinazolinoneand 0.850 g of{bis[alpha,alpha-bis(trifluoromethyl)benzenemethanolato]diphenylsulfur}in 5.0 ml of chloroform is stirred at room temperature for 3 hours. Thereaction mixture is diluted with chloroform and washed with 1N sodiumhydroxide and water. The organic layer is dried and evaporated in vacuoto a residue which is purified by column chromatography on silica gel byelution with 1:1 ethyl acetate-hexanes to give 0.599 g of the desiredproduct as a solid. FAB MASS SPEC 803 (M+Na)

EXAMPLE 29 Ethyl3-[2-butyl-3,4-dihydro-4-oxo-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-6-quinazolinyl]-2-propenoate

To a suspension of 1.75 g of ethyl3-(2-butyl-1,4-dihydro-4-oxo-6-quinazolinyl)-2-propenoate in 25 ml ofdry tetrahydrofuran at room temperature is rapidly added 6.70 g of a1.0M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran.After stirring for 20 minutes at room temperature 3.899 g of5-(4'-(bromomethyl)-[1,1'-biphenyl]-2-yl]-1-(triphenylmethyl)-1H-tetrazoleis rapidly added in one portion and the reaction mixture heated atreflux for 48 hours. After cooling to room temperature, the reactionmixture is diluted with ethyl acetate and the organic layer washed with5% HCl, water and brine. The organic layer is dried with MgSO⁴ andconcentrated in vacuo to a residue which is purified by columnchromatography on silicagel by eluting with 1:4 ethyl acetate-hexanes togive 1.732 g of the desired product as a solid. FAB MASS SPEC 799 (M+Na)

EXAMPLE 30 2-Butyl-6-(hydroxymethyl)-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl]-[1,1'-biphenyl]-4-yl]methyl-4(3H)-quinazolinone

A mixture of 0.198 g of 2-butyl-6-(hydroxymethyl)-4(1H)-quinazolinone,0.477 g of5-[4'-(bromomethyl)[1,1'-biphenyl]-2-yl]-1-(triphenylmethyl)-1H-tetrazoleand 0.500 g of potassium carbonate in 15.0 ml of dry acetone is heatedat reflux for 18 hours. The reaction mixture is allowed to cool to roomtemperature and evaporated to a residue. The residue is diluted withwater and extracted with chloroform. The organic layer is washed withbrine, dried with Na₂ SO₄ and evaporated in vacuo to a residue which ispurified on thick layer silica gel chromatography plates using 1:1 ethylacetate-hexanes to give 0.14 g of the desired product. FAB MASS SPEC 709(M+H)

EXAMPLE 31 2-Butyl-3,4-dihydro-4-oxo-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]-methyl)-6-quinazolinecarboxaldehyde

A mixture of 6.48 g of 2-Butyl-6-(hydroxymethyl)-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl]-[1,1'-biphenyl]-4-yl]methyl-4(3H)-quinazolinone and 5.16 g of pyridinium dichromate in 20 ml of methylenechloride is stirred at room temperature for 18 hours. The reactionmixture is diluted with 100 ml of ether and filtered through a short padof MGSO₄. The filtrate is concentrated in vacuo to give the desiredproduct as a residue. FAB MASS SPEC 729 (M+Na)

EXAMPLE 32 2-Butyl-6-(1-hydroxypropyl)-3-[]2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]-methyl]-4(3H)-quinazolinone

To a suspension of 1.00 g of2-Butyl-3,4-dihydro-4-oxo-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-6-quinazolinecarboxaldehydein 10 ml of tetrahydrofuran, cooled to -78° C. and 2.833 ml of a 1.0Msolution of ethylmagnesium bromide rapidly added. The cooling bath isremoved and the reaction mixture allowed to warm until a completesolution. The cooling bath is again applied and the reaction mixturecooled to -78° C. and stirred for 0.5 hours. The bath is removed and thereaction mixture allowed to reach room temperature. An aqueous solutionof ammonium chloride is added and the reaction mixture extracted withethyl acetate. The organic layer is dried and concentrated in vacuo togive 0.821 g of the desired product as a solid. FAB MASS SPEC 737 (M+H)

EXAMPLE 332-Butyl-6-(1-oxopropyl)-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl-4(3H)-quinazolinone

A mixture of 0.821 g of2-Butyl-6-(1-hydroxypropyl)-3-[[2'-[1-(triphenylmethyl-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinoneand 0.629 g of pyridinium dichromate in 2.5 ml of methylene chloride isstirred at room temperature for 20 hours. The reaction mixture isdiluted with ether and filtered through a short pad of MgSO₄.Thefiltrate is concentrated in vacuo to give 0.673 g of the desired productas a solid. FAB MASS SPEC 757 (M+Na)

EXAMPLE 34 2-Butyl-6-(1-methylenepropyl)-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]-methyl-4(3H)-quinazolinone

To a suspension of 1.169 g of methyltriphenylphosphonium bromide in 25ml of tetrahydrofuran, cooled to -78° C., is slowly added 1.74 ml of1.88 M n-butyllithium in hexanes. The reaction mixture is allowed towarm to room temperature and stirred until all of the phosphonium saltdissolves. This takes approximately 30 minutes. The reaction mixture iscooled to -78° C. and 0.803 g of2-Butyl-6-(1-oxopropyl)-3-[[2'-[1-(triphenylmethyl)-1H--tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl-4(3H)-quinazolinoneadded in one portion as a solid. The reaction mixture is allowed to warmto room temperature and stirred for 18 hours. The reaction mixture isquenched with saturated ammonium chloride, diluted with water andextracted with ethyl acetate. The organic layer is separated, washedwith brine, dried with MGSO and concentrated in vacuo to a residue whichis purified by chromatography on silica gel using 1:3 ethylacetate-hexanes to give 0.615 g of the desired product as a solid. FABMASS SPEC 755 (M+Na)

EXAMPLE 35 1-Hydroxy-pyrrolidine

To a stirred solution of 500 ml of ice water and 134 ml of pyrrolidineis added dropwise 230 ml of 30% hydrogen peroxide over 20 minutes withadditional ice cooling. When the addition is complete, the external bathis removed and the solution allowed to warm to 35° C. As the solutionapproaches 35° C. the temperature rapidly reaches 50° C. and externalice bath cooling is necessary. After the exotherm subsides, the coolingbath is removed and the reaction mixture stirred for 18 hours. Theaqueous solution is saturated with saturated sodium carbonate andextracted with methylene chloride. The organic layer is dried with NaSO₄and concentrated in vacuo to a residue which is diluted with 50 ml ofmineral oil and fractionally distilled to give 36 g of the desiredproduct as a colorless oil which solidifies when refrigerated, B.P.50°-55°/3 mm.

EXAMPLE 36 3,4-Dihydro-2H-pyrrole 1-oxide

To a solution of 0.300 g of 1-hydroxy-pyrrolidine in 10 ml of chloroformis rapidly added 1.49 g of yellow mercury(II)oxide in one portion as asolid. There is an exotherm. The reaction mixture is stirred for 2 hoursat room temperature and an additional 0.39 g of yellow mercury(II)oxideis added. After stirring for an additional 2 hours at room temperaturethe reaction mixture is filtered, the cake washed with chloroform andthe combined filtrates concentrated in vacuo to afford the desiredproduct.

EXAMPLE 37 2,3,4,5-Tetrahydro-pyridine 1-oxide

A mixture of 1.00 g of piperidine, 0.065 g of selenium dioxide and 2.64ml of 30% hydrogen peroxide in 25.0 ml of acetone is stirred at roomtemperature for 20 hours. The volatiles are evaporated in vacuo and theresidue diluted with water and extracted with chloroform. The organiclayer is dried over MgSO₄, filtered and evaporated in vacuo to a residuewhich is purified by column chromatography on silica gel by elution with9:1 chloroform-reethanol to give 0.155 g of the desired product as asolid.

EXAMPLE 38 3,4-Dihydro-isoquinoline 2-oxide

A mixture of 1.00 g of 1,2,3,4-tetrahydroisoquinoline, 0.042 g ofselenium dioxide, 2.30 ml of 30% hydrogen peroxide in 20 ml of methanolis stirred at room temperature for 20 hours. The reaction mixture isconcentrated in vacuo to a residue which is diluted with water andextracted with chloroform. The organic layer is dried and evaporated invacuo to a residue which is purified by column chromatography on silicagel by elution with 99:1 methanol-chloroform to give 0.703 g of thedesired product as a solid.

EXAMPLE 39CIS-(+/-)-2-Butyl-6-(hexahydroxypyrrolo[1,2-b]isoxazol-2-yl)-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone

To a solution of 1.291 g of2-Butyl-6-ethenyl-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl]-[1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinonein 100 ml of toluene is added 1.5 g of 3,4-Dihydro-2H-pyrrole 1-oxideand the reaction mixture heated at reflux for 6 hours. The reactionmixture is cooled and concentrated in vacuo to a residue which ispurified by chromatography on silica gel by elution with 8:1 ethylacetate-hexanes to give 0.906 g of the desired product as a white foam.FAB MASS SPEC 812 (X+Na)

EXAMPLE 40Cis-(+/-)-2-Butyl-6-(hexahydro-2-methylpyrrolo-[1,2-b]isoxazol-2-yl)-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,11-biphenyl]-4-yl]methyl]-4(3H)-quinazolineEXAMPLE 41Trans(+/-)-2-Butyl-6-(hexahydro-2-methylpyrrolo-[1,2-b]isoxazol-2-yl)-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone

To a solution of 0.500 g of2-Butyl-6-(1-methylethenyl)-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl-4(3H)-quinazolinonein 20 ml of toluene is added 0.600 g of 3,4-Dihydro-2H-pyrrole 1-oxideand the reaction mixture heated at reflux for 7 hours. The reactionmixture is cooled and concentrated in vacuo to a residue which ispurified by chromatography on silica gel by elution with 9:1 ethylacetate-hexanes to give 0.115 g of the first desired product FAB MASSSPEC 826 (M+Na), and with further elution 0.248 g of the second desiredproduct, FAB MASS SPEC 826 (M+Na).

EXMAPLE 42Cis-2-Butyl-6-(hexahydro-2H-isoxazolo[2,3-a]-pyridin-2-yl)-3-[[2'-[1-(triphonylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinoneEXAMPLE 43(Trans)-2-Butyl-6-(hexahydro-2H-isoxazolo[2,3-a]-pyridin-2-yl)-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone

To a solution of 0.500 g of2-Butyl-6-ethenyl-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl]-[1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinonein 100 ml of toluene is added 0.291 g of 2,3,4,5-tetrahydropyridine1-oxide and the reaction mixture heated at reflux for 18 hours. Thereaction mixture is cooled and concentrated in vacuo to a residue whichis purified by chromatography on silica gel by elution with 1:1 ethylacetate-hexanes to give 0.160 g of the first desired product as a foam,FAB MASS SPEC 826 (M+Na), and 0.057 g of the second desired product as afoam. FAB MASS SPEC 826 (M+Na).

EXAMPLE 44Cis(+/-)-2-Butyl-6-(hexahydro-6,6-dimethylpyrrolo[1,2-b]isoxazol-2-yl)-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone

To a solution of 0.500 g of2-Butyl-6-ethenyl-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl]-[1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinonein 25 ml of toluene is added 0.161 g of 5,5-dimethyl-1-pyrroline N-oxideand the reaction mixture heated at reflux for 6 hours. The reactionmixture is cooled and concentrated in vacuo to a residue which ispurified by chromatography on silica gel by elution with 2:1 ethylacetate-hexanes to give 0.332 g of the desired product. FAB MASS SPEC818 (M+H)

EXAMPLE 45 Ethyl2-[2-butyl-3,4-dihydro-4-oxo-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-6-quinazolinyl]hexahydro-pyrrolo[1,2-b]isoxazole-3-carboxylate

To a solution of 0.300 g of ethyl3-[2-butyl-3,4-dihydro-4-oxo-3-[[2'-[l-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-6-quinazolinyl]-2-propenoatein 20 ml of toluene is added 0.293 g of 3,4-dihydro-2H-pyrrole 1-oxideand the reaction mixture heated at reflux for 6 hours. The reactionmixture is cooled and concentrated in vacuo to a residue which ispurified by chromatography on silica reaction mixture heated at refluxfor 6 hours. The reaction mixture is cooled and concentrated in vacuo toa residue which is purified by chromatography on silica gel by elutionwith 1:1 ethyl acetate-hexanes to give 0.177 g of the desired product.FAB MASS SPEC 620 (M+H, --Ph3c).

EXAMPLE 46Cis-2-Butyl-6-(1,5,6,10b-tetrahydro-2H-isoxazolo[3,2-a]isoqruinolin-2-yl)-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone

To a solution of 0.500 g of ethyl3-[2-butyl-3,4-dihydro-4-oxo-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-6-quinazolinyl]-2-propenoatein 25 ml of toluene is added 0.313 g of 3,4-dihydro-isoquinoline 2-oxideand the reaction mixture heated at reflux for 12 hours. The reactionmixture is cooled and concentrated in vacuo to a residue which ispurified by chromatography on silica gel by elution vith 1:2 ethylacetate-hexanes to give 0.171 g of the desired product.

FAB MASS SPEC 874 (M+H).

EXAMPLE 47

Cis andTrans-2-Butyl-6-(1,5,6,10b-tetrahydro-2-methyl-2H-isoxazolo[3,2-a]isocruinolin-2-yl)-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,11-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone

To a solution of 0.250 g of2-Butyl-6-(1-methylethenyl)-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl-4(3H)-quinazolinonein 25 ml of toluene is added 0.300 g of 3,4-dihydro-isoquinoline 2-oxideand the reaction mixture heated at reflux for 16 hours. The reactionmixture is cooled and concentrated in vacuo to a residue which ispurified by chromatography on silica gel by elution with 1:2 ethylacetate-hexanes to give 0.201 g of the desired product. FAB KASS SPEC888 (M+Na).

EXAMPLE 48 2,3,4,5-Tetrahydro-6-methyl-pyridine 1-oxide

A mixture of 1.00 g of methyl piperidine, 0.056 g of selenium dioxideand 2.27 ml of 30% hydrogen peroxide in 20.0 ml of acetone is stirred atroom temperature for 20 hours. The volatiles are evaporated in vacuo andthe residue diluted with water and extracted with chloroform. Theorganic layer is dried over MGSO₄, filtered and evaporated in vacuo to aresidue which is purified by column chromatography on silica gel byelution with 9:1 chloroform-methanol to give 0.201 g of the desiredproduct as a solid.

EXAMPLE 49Cis-2-Butyl-6-(hexahydro-3a-methyl-2H-isoxazolo[2,3-a]pyridin-2-yl)-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone

To a solution of 0.500 g of2-Butyl-6-ethenyl-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,'1-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone in 25ml of toluene is added 0.201 g of 2,3,4,5-tetrahydro-6-methyl-pyridine1-oxide and the reaction mixture heated at reflux for 12 hours. Thereaction mixture is cooled and concentrated in vacuo to a residue whichis purified by chromatography on silica gel by elution with 1:2 ethylacetate-hexanes to give 0.108 g of the desired product.

EXAMPLE 50Cis(+/-)-2-Butyl-6-(hexahydro-2,6,6-trimethylpyrrolor[1,2-b]isoxazol-2-yl)-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinoneEXAMPLE 51Trans(+/-)-2-Butyl-6-(hexahydro-2,6,6-trimethylpyrolo[1,2-b]isoxazol-2-yl)-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]4(3H)-quinazolinone

To a solution of 0.500 g of 2-Butyl-6-(1-methylethenyl)-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl-4(3H)-quinazolinonein 25 ml of toluene is added 0.350 g of 5,5-dimethyl-1-pyrroline N-oxideand the reaction mixture heated at reflux for 7 hours. The reactionmixture is cooled and concentrated in vacuo to a residue which ispurified by chromatography on silica gel by elution with 1:2 ethylacetate-hexanes to give 0.064 g of the first desired product, FAB MASSSPEC 854 (M+Na), and with further elution 0.125 g of the second desiredproduct, FAB MASS SPEC 854 (M+Na).

EXAMPLE 52Cis-2-Butyl-6-(hexahydro-2-methyl-2H-isoxazolo[2,3-a]pyridin-2-yl)-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinoneEXAMPLE 53Trans-2-Butyl-6-(hexahydro-2-methyl-2H-isoxazolo[2,3-a]pyridin-2-yl)-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone

To a solution of 0.500 g of2-Butyl-6-(1-methylethenyl)-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl-4(3H)-quinazolinonein 20 ml of toluene is added 0.350 g of 2,3,4,5-tetrahydro-pyridine1-oxide and the reaction mixture heated at reflux for 12 hours. Thereaction mixture is cooled and concentrated in vacuo to a residue whichis purified by chromatography on silica gel by elution with 1:2 ethylacetate-hexanes to give 0.141 g of the first desired product, FAB MASSSPEC 840 (M+Na), and with further elution 0.096 g of the second desiredproduct, FAB MASS SPEC 840 (M+Na).

EXAMPLE 54Cis-2-butyl-6-(hexahydro-2-phenylpyrrolo[1,2-b]isoxazol-2-yl)-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone

To a solution of 0.569 g of2-Butyl-6-(1-phenylethenyl-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinolinonein 25 ml of toluene is added 0.733 g of 3,4-dihydro-2H-pyrrole 1-oxideand the reaction mixture heated at reflux for 17 hours. The reactionmixture is cooled and concentrated in vacuo to a residue which ispurified by chromatography on silica gel by elution with 1:1 ethylacetate-hexanes to give 0.131 g of the desired product. FAB MASS SPEC866 (M+H).

EXAMPLE 55Cis-2-butyl-6-(2-ethylhexahydropyrrolo[1,2-b]isoxazol-2-yl)-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinoneEXAMPLE 56Trans-2-butyl-6-(2-ethylhexahydrpyrrolo[1,2-b]isoxazol-2-yl)-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone

To a solution of 0.605 g of2-Butyl-6-(1-methylenepropyl)-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl-4(3H)quinazolinonein 30 ml of toluene is added 0.85 g of 3,4-dihydro-2H-pyrrole 1-oxideand the reaction mixture heated at reflux for 16 hours. The reactionmixture is cooled and concentrated in vacuo to a residue which ispurified by high pressure liquid chromatography on silica gel by elutionwith 2:1 ethyl acetate-hexanes to give 0.146 g of the first desiredproduct, FAB MASS SPEC 840 (M+Na), and 0.284 g of the second desiredproduct. FAB MASS SPEC 840 (M+Na).

EXAMPLE 57Cis-(+/-)-2-Butyl-6-(hexahydropyrrolo[1,2-b]isoxazol-2-yl)-3-[[21-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone

To a solution of 0.886 g ofCIS-(+/-)-2-Butyl-6-(hexahydropyrrolo[1,2-b]isoxazol-2-yl)-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinonedissolved in 2.0 ml of tetrahydrofuran is added 10.0 ml of methanol. Thereaction mixture is heated at reflux for 18 hours, cooled andconcentrated in vacuo to a residue which is purified by chromatographyon silica gel using 9:1 chloroform-methanol to give 0.534 g of thedesired product as a white foam. FAB MASS SPEC 548 (M+H)

EXAMPLE 58Cis-(+/-)-2-Butyl-6-(hexahydro-2-methyloyrrolo[1,2-b]isoxazol-2-yl)-3-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone

A solution of 0.082 g ofCis-(+/-)-2-Butyl-6-(hexahydro-2-methylpyrrolo[1,2-b]isoxazol-2-yl)-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinonein 2.0 ml of methanol and 0.5 ml of tetrahydrofuran is heated at refluxfor 18 hours, cooled, and concentrated in vacuo to a residue which ispurified by column chromatography on silica gel by elution with 99:1 to9:1 chloroform-methanol to give 0.026 g of the desired product as asolid. FAB MASS SPEC 562 (M+H).

EXAMPLE 59Trans-2-Butyl-6-(hexahydro-2-methylpyrrolo[1,2-b]isoxazol-2-yl)-3-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone

A solution of 0.248 9 oftrans-2-butyl-6-(hexahydro-2-methylpyrrolo-[1,2-b]isoxazol-2-yl)-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-bi-phenyl]-4-yl]methyl]-4(3H)-quinazolinone,5.0 ml of methanol and 1.0 ml of tetrahydrofuran is heated at reflux for18 hours, cooled, and concentrated in vacuo to a residue which ispurified by column chromatography on silica gel by elution with 9:1chloroform-methanol to give 62 mg of the desired product as a solid. FABMASS SPEC 562 (M+H).

EXAMPLE 60Cis-2-Butyl-6-(hexahydro-2H-isoxazolor2,3-a]pyridin-2-yl)-3-[[2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone

A solution of 0.148 g ofCis-2-butyl-6-(hexahydro-2H-isoxazolo[2,3-a]pyridin-2-yl)-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinonein 5.0 ml of mothanol and 1.0 ml of tetrahydrofuran is heated at refluxfor 4 hours. The volatiles are evaporated in vacuo to a residue which ispurified by column chromatography on silica gel by elution with 99:1 to9:1 chloroformmethanol to give 0.065 g of the desired product as asolid. FAB MASS SPEC 562 (M+H).

EXAMPLE 61Cis-2-Butyl-6-(hexahydro-6,6-dimethylpyrrolo[1,2-b]isoxazol-2-yl)-3-[[2'-(1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone

A solution of 0.320 g ofCis-2-butyl-6-(hexahydro-6,6-dimethylpyrrolo[1,2-b]isoxazol-2-yl)-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinonein 5.0 ml of methanol and 1.0 ml of tetrahydrofuran is heated at refluxfor 18 hours. The volatiles are evaporated in vacuo to a residue whichis purified by column chromatography on silica gel by elution with 99:1to 9:1 chloroform-methanol to give 0.194 g of the desired product as asolid. FAB MASS SPEC 576 (M+H).

EXAMPLE 62 Ethyl 2-[2-butyl-3.4-dihydro-4-oxo-3-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-6-quinazolinyl]hexahydro-pyrrolo[1,2-b]isoxazole-3-carbolcylate

A solution of 0.174 g of ethyl2-[2-butyl-3,4-dihydro-4-oxo-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-6-quinazolinyl]hexahydro-pyrrolo[1,2-b]isoxazole-3-carboxylatein 2.0 ml of ethanol and 1.0 ml of chloroform containing 2.0 ml of 3MHCl in ethyl acetate is stirred at room temperature for 1 hour. Thevolatiles are evaporated in vacuo to a residue which is purified bycolumn chromatography on silica gel by elution with 9:1chloroform-methanol to give 0.063 g of the desired product as a solid.FAB MASS SPEC 620 (M+H).

EXAMPLE 63Cis-2-Butyl-6-(1,5,6,10b-tetrahydro-2H-isoxazolo[3,2-a]isoquinolin-2-yl)-3-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone

A solution of 0.134 g ofCis-2-butyl-6-(1,5,6,10b-tetrahydro-2H-isoxazolo[3,2-a]isoquinolin-2-yl)-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinonein 2.5 ml of methanol and 0.5 ml of tetrahydrofuran is heated at refluxfor 18 hours. The volatiles are evaporated in vacuo to a residue whichis purified by column chromatography on silica gel by elution with 99:1chloroform-methanol to give 0.082 g of the desired product as a solid.FAB MASS SPEC 610 (M+H).

EXAMPLE 64 Cis andTrans-2-Butyl-6-(1,5,6,10b-tetrahydro-2-methyl-2H-isoxazolo[3,2-a]isoquinolin-2-yl)-3-[[2'-(1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone

A solution of 0.185 g of Cis andTrans-2-Butyl-6-(1,5,6,10b-tetrahydro-2-methyl-2H-isoxazolo[3,2-a]isoquinolin-2-yl)-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-4(3H-quinazolinonein 5.0 ml of methanol and 1.0 ml of tetrahydrofuran is heated at refluxfor 18 hours. The volatiles are evaporated in vacuo to a residue whichis purified by column chromatography on silica gel by elution with 9:1chloroform-methanol to give 0.118 g of the desired product as a solid.FAB MASS SPEC 624 (M+H)

EXAMPLE 65Cis-2-Butyl-6-(hexahydro-3a-methyl]-2H-isoxazolo[2,3-a]pyridin-3-yl)-3-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone

A solution of 0.089 g ofcis-2-butyl-6-(hexahydro-3a-methyl-2H-isoxazolo[2,3-a]pyridin-2-yl)-3-[[2'-[1-(triphenylmethyl)-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinonein 2.5 ml of methanol and 0.5 ml of tetrahydrofuran is heated at refluxfor 16 hours. The volatiles are evaporated in vacuo to a residue whichis purified by column chromatography on silica gel by elution with 99:1chloroform-methanol to give 0.046 g of the desired product as a solid.FAB MASS SPEC 576 (M+H).

EXAMPLE 66Cis-2-Butyl-6-(hexahydro-2,6,6-trimethylpyrrolo[1;2-b]isoxazol-2-yl)-3-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone

A solution of 0.097 g ofCis-2-butyl-6-(hexahydro-2,6,6-trimethylpyrrolo[1,2-b]isoxazol-2-yl)-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinonein 2.5 ml of methanol and 0.5 ml of tetrahydrofuran is heated at refluxfor 18 hours. The volatiles are evaporated in vacuo to a residue whichis purified by column chromatography on silica gel by elution with 99:1chloroform-methanol to give 0.018 g of the desired product as a solid.FAB MASS SPEC 590 (M+H).

EXAMPLE 67Cis-2-Butyl-6-(hexahydro-2-methyl-2H-isoxazolo[2,3-a]pyridin-2-yl)-3-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone

To a solution of 0.131 g ofCis-2-butyl-6-(hexahydro-2-methyl-2H-isoxazolo[2,3-a]pyridin-2-yl)-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1,-biphenyl]-4-yl]methyl]-4(3H)-quinazolinonein 5.0 ml of methanol and 1.0 ml of tetrahydrofuran is heated at refluxfor 18 hours. The volatiles are evaporated in vacuo to a residue whichis purified by column chromatography on silica gel by elution with 99:1chloroform-methanol to give 0.083 g of the desired product as a solid.FAB MASS SPEC 576 (M+H).

EXAMPLE 68Trans-2-Butyl-6-(hexahydro-2-methyl-2H-isoxazolo[2,3-a]pyridin-2-yl)-3-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone

A solution of 0.087 g ofTrans-2-butyl-6-(hexahydro-2-methyl-2H-isoxazolo[2,3-a]pyridin-2-yl)-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'biphenyl]-4-yl]methyl]-4(3H)-quinazolinonein 5.0 ml of methanol and 1.0 ml of tetrahydrofuran is heated at refluxfor 5 hours. The volatiles are evaporated in vacuo to a residue which ispurified by column chromatography on silica gel by elution with 99:1chloroform-methanol to give 0.057 g of the desired product as a solid.FAB MASS SPEC 576 (M+H).

EXAMPLE 69Trans-2-Butyl-6-(hexahydro-2,6,6-trimethpyrrolo[1,2-b]isoxazol-2-yl)-3-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone

A solution of 0.115 g ofTrans-2-butyl-6-(hexahydro-2,6,6-trimethylpyrrolo[1,2-b]isoxazol-2-yl)-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl]1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone in 5.0 ml of methanol and 1.0 ml of tetrahydrofuran isheated at reflux for 16 hours. The volatiles are evaporated in vacuo toa residue which is purified by column chromatography on silica gel byelution vith 99:1 chloroform-methanol to give 0.069 g of the desiredproduct as a solid. FAB RASS SPEC 590 (M+H).

EXAMPLE 70Cis-2-butyl-6-(hexahydro-2-phenylpyrrolo[1,2-b]isoxazol-2-yl)-3-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone

A solution of 0.105 g ofCis-2-butyl-6-(hexahydro-2-phenylpyrrolo[1,2-b]isoxazol-2-yl)-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinonein S.0 ml of methanol and 1.0 ml of tetrahydrofuran is heated at refluxfor 18 hours. The volatiles are evaporated in vacuo to a residue whichis purified by column chromatography on silica gel by elution with 99:1chloroform-methanol to give 0.047 g of the desired product as a solid.FAB MASS SPEC 624 (M+H).

EXAMPLE 71Cis-2-butyl-6-(2-ethylhexahydropyrrolo[1,2-b]isoxazol-2-yl)-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl)][1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone

To a solution of 0.073 g ofCis-2-butyl-6-(2-ethylhexahydropyrrolo[1,2-b]isoxazol-2-yl)-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinonein 5.0 ml of methanol and 1.0 ml of tetrahydrofuran is heated at refluxfor 16 hours. The volatiles are evaporated in vacuo to a residue whichis purified by column chromatography on silica gel by elution with 9:1chloroform-methanol to give 0.037 g of the desired product as a solid.FAB MASS SPEC 576 (M+H).

EXAMPLE 72Trans-2-butyl-6-(2-ethylhexahydropyrrolo[1,2-b]isoxazol-2-yl)-3-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone

To a solution of 0.266 g ofTrans-2-butyl-6-(2-ethylhexahydropyrrolo[1,2-b]-isoxazol-2-yl)-3-[[2'-2-[1-(triphenylmethyl)-1H-tetrazol-5yl][1,1'-biphenyl]-4yl]methyl]-4-(3H)-quinazolinonein 5.0 ml of methanol and 1.0 ml of tetrahydrofuran is heated at refluxfor 16 hours. The volatiles are evaporated in vacuo to a residue whichis purified by column chromatography on silica gel by elution with 9:1chloroform-methanol to give 0.097 g of the desired product as a solid.FAB MASS SPEC 576 (M+H).

EXAMPLE 73Cis-2-Butyl-6-(hexahydro-2-methypyrrolo[1,2-b]isoxazol-2-yl)-3-[[2'-(1H-(tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinonesodium salt

A solution of 0.597 g ofCis-2-butyl-6-(hexahydro-2-methylpyrrolo[1,2-b]isoxazol-2-yl)-3-[[2'-(1H-(tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinoneand 1.064 ml of 1N sodium hydroxide in 10 ml of methyl alcohol isstirred at room temperature for I hour. The volatiles are evaporated invacuo to a solid which is dried to give 0.62 g of the desired product.FAB MASS SPEC 584 (M+H).

EXAMPLE 74Cis-2-Butyl-6-(hexahydro-2-methylpyrrolo[1,2-b]isoxazol-2-yl)-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone

To a suspension of 0.050 g ofCis-2-Butyl-6-(hexahydro-2,6,6-trimethylpyrrolo[1,2-b]isoxazol-2-yl)-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinonesodium salt in 2.5 ml of methylene chloride containing 13 ul oftriethylamine is added 0.025 g of triphenylmethyl chloride and thereaction mixture heated at reflux for 2 hours. The cooled reactionmixture is diluted with water and extracted with methylene chloride. Theorganic extract is dried over MgSO₄ and evaporated in vacuo to a residuewhich is purified by column chromatography on silica gel using ethylacetate to give 0.053 g of the desired product as a solid. FAB MASS SPEC826 (M+Na).

EXAMPLE 752-Butyl-3,4-dihydro-a-methylene-4-oxo-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl-6-quinazolineacetic acid

To a stirred mixture of 1.00 g of6-acetyl-2-butyl-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone,0.50 ml of water, 0.345 g of benzyltrimethylammonium chloride, 0.345 gof sodium hydroxide, 3 mg of benzyl alcohol and 4.0 ml of methylenechloride is added 0.414 ml of chloroform via a syringe pump over 6hours. The reaction mixture is stirred at room temperature. The reactionmixture is diluted with 5% HCI and extracted with chloroform. Theorganic layer is dried with Na₂ SO₄ and evaporated to a residue which ispurified by column chromatography on silica gel by elution with 2:1ethyl acetate-hexanes to give 0.115 g of the desired product. FAB MASSSPEC 771 (M+Na).

EXAMPLE 76 Methyl2-bUtyl-α-methylone-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl-6-quinazoline acetate

To a solution of 0.100 g of6-acetyl-2-butyl-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone,0.013 g of 4-dimethylaminopyridine in 2.0 ml of methylene chloride and0.055 ml of methanol, cooled to 0° C. is added 0.030 g ofdicyclohexylcarbodiimide as a solid. The reaction mixture is allowed towarm to room temperature and stirred for 18 hours. The reaction mixtureis quenched with 5% HCl and extracted with methylene chloride. Theorganic layer is washed with 5% HCl, water and saturated sodiumbicarbonate. The organic layer is dried with Na₂ SO₄ and evaporated to aresidue. The residue is purified by column chromatography on silica byelution with 1:4 ethyl acetate-hexanes to give 0.052 g of the desiredproduct.

FAB MASS SPEC 785 (M+Na).

EXAMPLE 77(Trans)-methyl-2-[2-butyl-3,4-dihydro-4-oxo-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-6-quinazolinyllhexahydropyrrolo[1,2-b]isoxazole-2-carboxylate

A solution of 1.781 g of methyl2-butyl-α-methylene-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl-6-quinazolineacetate, 9 of 3,4-dihydro-2H-pyrrole 1-oxide in 150 ml of chloroform isheated at reflux for 1.5 hours. The volatiles are evaporated to aresidue which is purified by column chromatography on silica gel byelution with 1:2, 1:1 and 2:1 ethyl acetate-hexanes to give 1.491 g ofthe desired product. FAB MASS SPEC 848 (M+H)

EXAMPLE 78(Trans)(+/-)-Methyl-2-[2-butyl-3,4-dihydro-4-oxo-3-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl-6-quinazolinyl]hexahydropyrrolo[1,2-b]isoxazole-2-carboxylate

A mixture of 0.100 g of(trans)-methyl-2-[2-butyl-3,4-dihydro-4-oxo-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-6-quinazolinyl]hexahydropyrrolo-[1,2-b]isoxazole-2-carboxylatein 2.0 ml of 3M HCl in ethyl acetate and 2.0 ml of ether is stirred atroom temperature for 15 minutes. The reaction mixture is diluted with 2ml of 1:1 ether-hexanes and the resulting solid filtered and dried togive 0.075 g of the desired product as a solid. FAB MASS SPEC 606 (M+H,--HCl).

EXAMPLE 79CIS-2-Butyl-6-[1-hydroxy-1-methyl-2-(2-pyrrolidinyl)ethyl]-3-[[21-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone

A mixture of 0.050 g ofcis-2-butyl-6-(hexahydro-2-methylpyrrolo[1,2-b]isoxazol-2-yl)-3-[[2'-(1H-(tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinonesodium salt, 0.063 g of zinc powder and 2.0 ml of 1:1 acetic acid-wateris heated at 65° C. for 5 hours. The reaction mixture is cooled, dilutedwith water and filtered. The filter cake is dissolved in methyl alcoholand evaporated in vacuo to a residue which is purified by thick layerreverse phase preparative chromatography. The plate is eluted with 0.1Mammonium formate at pH 3 (67%) and acetonitrile (33%) to obtain 0.020 gof the desired product as a solid. FAB MASS SPEC 564 (M+H).

EXAMPLE 80CIS-(+/-)-2-Butyl-6-[1-hydroxy-2-(2-pyrrolidinyl)ethyl]-3-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone

A mixture of 0.400 g ofcis-(+/-)-2-butyl-6-(hexahydropyrrolo[1,2-b]isoxazol-2-yl)-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]-methyl]-4(3H)-quinazolinone,0.372 g of zinc and 4.0 ml of 1:1 acetic acid-water is heated at 65° C.for 5 hours. The reaction mixture is cooled, diluted vith 50 ml of waterand filtered. The filter cake is dissolved in methyl alcohol andevaporated in vacuo to a residue. A 50 mg sample is purified by thicklayer reverse phase preparative chromatography. Two plates are elutedwith 01.M ammonium formate at pH 3 (66%) and acetonitrile 33%, to obtain20 mg of the desired product as a solid.

FAB MASS SPEC 550 (M+H).

EXAMPLE 81trans-2-butyl-6-[1-hydroxy-1-methyl-2-(2-pyrrolidinyl)ethyl]-3-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone

The desired product is obtained from the product of Example 59,substantially utilizing the procedure of Example 79.

EXAMPLE 822-butyl-6-[1-hydroxy-2-(2-piperidinyl)ethyl]-3-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone

The desired product is obtained from the product of Example 60,substantially utilizing the procedure of Example 79.

EXAMPLE 832-butyl-6-[2-(5,5-dimethyl-2-pyrrolidinyl)-1-hydroxyethyl]-3-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone

The desired product is obtained from the product of Example 61,substantially utilizing the procedure of Example 79.

EXAMPLE 84 ethyl2-butyl-3,4-dihydro-(3-hydroxy-4-oxo-2-pyrrolidinyl)-3-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinepropionate

The desired product is obtained from the product of Example 62,substantially utilizing the procedure of Example 79.

EXAMPLE 852-butyl-6-[1-hydroxy-2-(1,2,3,4-tetrahydro-1-isocruinolinyl)ethyl]-3-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]4-yl]-methyl]-4(3H)-quinazolinone

The desired product is obtained from the product of Example 63,substantially utilizing the procedure of Example 79.

EXAMPLE 862-butyl-6-[1-hydroxy-1-methyl-2-(1,2,3,4-tetrahydro-1-isoquinolinyl)ethyl]-3-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]-methyl]-4(3H)-quinazolinone

The desired product is obtained from the product of Example 64,substantially utilizing the procedure of Example 79.

EXAMPLE 872-butyl-6-[1-hydroxy-2-(2-methyl-2-piperidinyl)ethyl]-3-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl-4-yl]-methyl]-4(3H)-quinazolinone

The desired product is obtained from the product of Example 65,substantially utilizing the procedure of Example 79.

EXAMPLE 882-butyl-6-[2-(5,5-dimethyl-2-pyrrolidinyl)-1-hydroxy-1-methylethyl]-3-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]-methyl]-4(3H)-quinazolinone

The desired product is obtained from the product of Example 66,substantially utilizing the procedure of Example 79.

EXAMPLE 892-butyl-6-[1-hydrogy-1-methyl-2-(2-piperidinyl)ethyl]-3-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyll-4-yl]-methyl]-4(3H)-quinazolinone

The desired product is obtained from the product of Example 67,substantially utilizing the procedure of Example 79.

EXAMPLE 902-butyl-6-[1-hydroxy-1-methyl-2-(2-piperidinyl)ethyl]-3-[[2l-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone

The desired product is obtained from the product of Example 68,substantially utilizing the procedure of Example 79.

EXAMPLE 912-butyl-6-[2-(5,5-dimethyl-2-pyrrolidinyl)-1-hydroxy-1-methylethyl]-3-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]-methyl]-4(3H)-quinazolinone

The desired product is obtained from the product of Example 69,substantially utilizing the procedure of Example 79.

EXAMPLE 922-butyl-6-[1-hydroxy-1-phenyl-2-(2-pyrrolidinyl)ethyl]-3-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyll-4-yl]-methyl]-4(3H)-quinazolinone

The desired product is obtained from the product of Example 70,substantially utilizing the procedure of Example 79.

EXAMPLE 932-butyl-6-[1-hydroxy-1-(2-pyrrolidinylmethyl)propyl-3-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]-methyl]-4(3H)-quinazolinone

The desired product is obtained from the product of Example 71,substantially utilizing the procedure of Example 79.

EXAMPLE 942-butyl-6-[1-hydroxy-1-(2-pyrrolidinylmethyl)vropyll-3-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]-methyl]-4(3H)-quinazolinone

The desired product is obtained from the product of Example 72,substantially utilizing the procedure of Example 79.

ANGIOTENSIN II ANTAGONISTS IN VITRO TESTS MATERIALS AND METHODS

Beef adrenals are obtained from a local slaughter house (Maxwell-Cohen).[¹²⁵ I](Sar¹,Ile⁸)AngII, S. A. 2200 Ci/mmole, is purchased from Dupont(NEN®, Boston, Mass.). All unlabeled AngII analogs, Dimethylsulfoxide(DMSO), nucleotides, bovine serum albumin (BSA) are purchased from SigmaChemical Co., St. Louis, Mo. U.S.A.

PREPARATION OF MEMBRANES

Approximately sixteen (16) to twenty (20) beef adrenal glands areprocessed as follows: fresh adrenal glands received on crushed ice arecleaned of fatty tissues and the tough membranes encapsulating theglands are removed and discarded. The brownish tissue forming theadrenal cortex is scraped off and finely minced with scissors beforehomogenization. care is taken to avoid contamination vith medullarytissue during dissection. The scraped cortices are suspended in twentyvolumes of an ice-cold buffer medium consisting of 10 Mm Tris.HCl (pH7.4 at 22° C.) and containing 1.0 Mm EDTA and 0.2M sucrose. Unlessotherwise indicated, all subsequent operations are done at 4° C. Thetissue is homogenized in a glass homogenizer with a motor-driven teflonpestle with a clearance of 1.0 mm. The homogenate is centrifuged firstat low speed (3,000 x g) for 10 min. The resulting pellet is discardedand the supernatant fluid recentrifuged at 10,000 x g for 15 minutes togive a P₂ pellet. This P₂ pellet is discarded and the liquid phase iscarefully decanted off in clean centrifuge tubes and recentrifuged athigh speed (100,000 x g) for 60 min. The translucent final pellet isharvested and combined in a small volume (20-50.0 ml) of 50.0 MmTris.HCl buffer, pH 7.2. A 100 ul aliquot is withdrawn and the proteincontent of the preparation is determined by the Lowry's method (Lowry,O. H., Rosebrough, N. P., Farr, A. L. and Randall, R. J., Proteinmeasurement with Polin phenol reagent. J. Biol. Chem., 48, 265-275,1951). The pelleted membrane is reconstituted in 50.0 mM Tris.HCl buffercontaining 0.1 mM of phenylmethylsulfonyl fluoride (PMSF) to giveapproximately a protein concentration of 2.5 mg per ml of tissuesuspension. The membrane preparation is finally aliquoted in 1.0 mlvolumes and stored at -70° C. until use in the binding assays.

RECEPTOR BINDING ASSAY Binding of [¹²⁵ I](Sar¹,Ile⁸)AngII

The binding of [¹²⁵ I](Sar¹ Ile⁸)AngII to microsomal membranes isinitiated by the addition of reconstituted membranes (1:10 vols.) infreshly made 50.0 mM Tris.HCl buffer, pH 7.4 containing 0.25% heatinactivated bovine serum albumin (BSA): 80 ul membrane protein (10 to 20ug/assay) to wells already containing 100 ul of incubation buffer (asdescribed above) and 20 ul [¹²⁵ I](Sar¹ Ile⁸)AngII (Specific Activity,2200 Ci/mmole). Non-specific binding is measured in the presence of 1.0uM unlabeled (Sar¹,Ile⁸)AngII, added in 20 ul volume. Specific bindingfor [¹²⁵ I](Sar¹ Ile⁸ AngII is greater than 90%. In competition studies,experimental compounds are diluted in dimethylsulfoxide (DMSO) and addedin 20 ul to wells before the introduction of tissue membranes. Thisconcentration of DMSO is found to have no negative effects on the 30binding of [125 I](Sar1Ile8) AngII to the membranes. Assays areperformed in triplicate. The wells are left undisturbed for 60 min. atroom temperature. Following incubation, all wells are harvested at oncewith a Brandel® Harvester especially designed for a 96 well plate(Brandel® Biomedical Research & Development Labs. Inc., Gaithersburg,Md., U.S.A.). The filter discs are washed with 10×1.0 mi of cold 0.9%NaCl to remove unbound ligand. Presoaking the filter sheet in 0.1%polyethyleneimine in normal saline (PEI/Saline) greatly reduces theradioactivity retained by the filter blanks. This method is routinelyused. The filters are removed from the filter grid and counted in aParkard® Cobra GAmma counder for 1 min. (Packard Instrument Co., DownersGrove, Ill., U.S.A.). The binding data are analyzed by the non-linearinteractive "LUNDON-1" program (LUNDON SOFTWARE Inc., Cleveland, OhioU.S.A.). Compounds that displace 50% of the labelled angiotensin II atthe screening dose of 50 μM are considered active compounds and are thenevaluated in concentration-response experiments to determine their IC₅₀values. The results are shown in Table I.

                  TABLE I                                                         ______________________________________                                         ##STR27##                                                                                                    Angiotensin II                                Ex.                             Receptor                                      No.  R.sup.6         X          Binding IC.sub.50 (M)                         ______________________________________                                        79                                                                                  ##STR28##      (CH.sub.2).sub.3 CH.sub.3                                                                 3.5 × 10.sup.-9                        80                                                                                  ##STR29##      (CH.sub.2).sub.3 CH.sub.3                                                                41.0 × 10.sup.-9                        ______________________________________                                    

As can be seen from the above table, the compounds demonstrate excellentactivity.

The enzyme renin acts on a blood plasma α₂ -globulin, angiotensinogen,to produce angiotensin I, which is then converted by angiotensinconverting enzyme to AII. The substance AII is a powerful vasopressoragent which is implicated as a causative agent for producing high bloodpressure in mammals. Therefore, compounds which inhibit the action ofthe hormone angiotensin II (AII) are useful in alleviating angiotensininduced hypertension.

As can be seen from Table I, the compounds demonstrate excellentAngiotensin II Receptor Binding activity.

The enzyme renin acts on a blood plasma α₂ -globulin, angiotensinogen,to produce angiotensin I, which is then converted by angiotensinconverting enzyme to AII. The substance AII is a powerful vasopressoragent which is implicated as a causative agent for producing high bloodpressure in mammals. Therefore, compounds which inhibit the action ofthe hormone angiotensin II (AII) are useful in alleviating angiotensininduced hypertension.

The compounds of this invention inhibit the action of AII. Byadministering a compound of this invention to a rat, and thenchallenging with angiotensin II, a blockage of the vasopressor responseis realized. The results of this test on representative compounds ofthis invention are shown in Table II.

AII CHALLENGE

Conscious Male Okamoto-Aoki SHR, 16-20 weeks old, weighing approximately330 g are purchased from Charles River Labs (Wilmington, Mass.).Conscious rats are restrained in a supine position with elastic tape.The area at the base of the tail is locally anesthetized by subcutaneousinfiltration with 2% procaine. The ventral caudal artery and vein areisolated, and a cannula made of polyethylene (PE) 10-20 tubing (fusedtogether by heat) is passed into the lower abdominal aorta and venacava, respectively. The cannula is secured, heparinized (1,000 I.U./ml),sealed and the wound is closed. The animals are placed in plasticrestraining cages in an upright position. The cannula is attached to aStatham P23Db pressure transducer, and pulsatile blood pressure isrecorded to 10-15 minutes with a Gould Brush recorder. (Chan et al.,(Drug Development Res., 18:75-94, 1989).

Angiotensin II (human sequence, Sigma Chem. Co., St. Louis, Mo.) of 0.05and 0.1 ug/kg i.v. is injected into all rats (predosing response). Thena test compound, vehicle or a known angiotensin II antagonist isadministered i.v., i.p. or orally to each set of rats. The two doses ofangiotensin II are given to each rat again at 30, 60, 90, 120, 180, 240and 300 minutes post dosing the compound or vehicle. The vasopressorresponse of angiotensin II is measured for the increase in systolicblood pressure in mmhg. The percentage of antagonism or blockade of thevasopressor response of angiotensin II by a compound is calculated usingthe vasopressor response (increase in systolic blood pressure) ofangiotensin II of each rat predosing the compound as 100%. A compound isconsidered active if at 30 mg/kg i.v. it antagonized at least 50% of theresponse.

    __________________________________________________________________________    ANGIOTENSIN II (AII) VASOPRESSOR RESPONSE                                     __________________________________________________________________________           Dose AII Dose                                                                            Min Post                                                                           Control                                                                             Response   Average                                                                            %                                       (mg/kg)                                                                            mcg/kg IV                                                                           Dose Before AII                                                                          After AII                                                                           Change                                                                             Change                                                                             Inhibition                       __________________________________________________________________________    CONTROL     0.05   0   215   250   35   37.5                                                         205   245   40                                                     0.1        210   260   50   45                                                           205   245   40                                         Ex. No.                                                                              1 I.V.                                                                             0.05  30   200   200    0   2.5  93                               79                     200   205    5                                                     0.1        190   205   15   11   76                                                      195   202    7                                                     0.05  60   205   220   15   12.5 67                                                      195   205   10                                                     0.1        195   214   19   17   62                                                      195   210   15                                                     0.05  90   200   215   15   17.5 53                                                      200   220   20                                                     0.1        195   220   25   20   56                                                      200   215   15                                                     0.05  120  195   215   20   20   47                                                      195   215   20                                                     0.1        200   230   30   27.5 39                                                      195   220   25                                                     0.05  180  205   220   15   17.5 53                                                      195   215   20                                                     0.1        195   225   30   22.5 50                                                      205   220   15                                         __________________________________________________________________________     SPONTANEOUSLY HYPERTENSIVE RATES n = 2                                        Body weight(s): 320, 315 grams                                           

           Dose AII Dose                                                                            Min Post                                                                           Control                                                                             Response   Average                                                                            %                                       (mg/kg)                                                                            mcg/kg IV                                                                           Dose Before AII                                                                          After AII                                                                           Change                                                                             Change                                                                             Inhibition                       __________________________________________________________________________                0.05  240  195   220   25   30   20                                                      200   235   35                                                     0.1        205   238   33   34   24                                                      205   240   35                                         CONTROL     0.05   0   235   260   25   27.5                                                         240   270   30                                                     0.1        235   260   25   27.5                                                         245   275   30                                         Ex. No.                                                                              2 P.O.                                                                             0.05  30   230   260   30   27.5  0                               79                     250   275   25                                                     0.1        235   265   30   30   -9                                                      245   275   30                                                     0.05  60   235   265   30   30   -9                                                      240   270   30                                                     0.1        225   260   35   37.5 -36                                                     240   280   40                                                     0.05  90   225   245   20   24   13                                                      230   258   28                                                     0.1        225   270   45   42.5 -55                                                     230   270   40                                                     0.05  120  225   242   17   23.5 15                                                      235   265   30                                                     0.1        224   255   31   30.5 -11                                                     240   270   30                                         __________________________________________________________________________     SPONTANEOUSLY HYPERTENSIVE RATS n = 2                                         Body weight(s): 300, 310 grams                                           

    Dose        AII Dose                                                                            Min Post                                                                           Control                                                                             Response   Average                                                                            %                                       (mg/kg)                                                                            mcg/kg IV                                                                           Dose Before AII                                                                          After AII                                                                           Change                                                                             Change                                                                             Inhibition                       __________________________________________________________________________                0.05  180  235   252   17   26    5                                                      240   275   35                                                     0.1        230   262   32   38.5 -40                                                     235   280   45                                         __________________________________________________________________________

When the compounds are employed for the above utility, they may becombined with one or more pharmaceutically acceptable carriers, forexample, solvents, diluents and the like, and may be administered orallyin such forms as tablets, capsules, dispersible powders, granules, orsuspensions containing, for example, from about 0.05 to 5% of suspendingagent, syrups containing, for example, from about 10 to 50% of sugar,and elixirs containing, for example, from about 20 to 50% ethanol, andthe like, or parenterally in the form of sterile injectable solutions orsuspension containing from about 0.05 to 5% suspending agent in anisotonic medium. Such pharmaceutical preparations may contain, forexample, from about 0.05 up to about 90% of the active ingredient incombination with the carrier, more usually between about 5% and 60% byweight.

The effective dosage of active ingredient employed may vary depending onthe particular compound employed, the mode of administration and theseverity of the condition being treated. However, in general,satisfactory results are obtained when the compounds of the inventionare administered at a daily dosage of from about 0.5 to about 500 mg/kgof animal body weight, preferably given in divided doses two to fourtimes a day, or in sustained release form. For most large mammals thetotal daily dosage is from about 1 to 100 mg, preferably from about 2 to80 mg. Dosage forms suitable for internal use comprise from about 0.5 to500 mg of the active compound in intimate admixture with a solid orliquid pharmaceutically acceptable carrier. This dosage regimen may beadjusted to provide the optimal therapeutic response. For example,several divided doses may be administered daily or the dose may beproportionally reduced as indicated by the exigencies of the therapeuticsituation.

These active compounds may be administered orally as well as byintravenous, intramuscular, or subcutaneous routes. Solid carriersinclude starch, lactose, dicalcium phosphate, microcrystallinecellulose, sucrose and kaolin, while liquid carriers include sterilewater, polyethylene glycols, non-ionic surfactants and edible oils suchas corn, peanut and sesame oils, as are appropriate to the nature of theactive ingredient and the particular form of administration desired.Adjuvants customarily employed in the preparation of pharmaceuticalcompositions may be advantageously included, such as flavoring agents,coloring agents, preserving agents, and antioxidants, for example,vitamin E, ascorbic acid, BHT and BHA.

The preferred pharmaceutical compositions from the standpoint of ease ofpreparation and administration are solid compositions, particularlytablets and hard-filled or liquid-filled capsules. Oral administrationof the compounds is preferred.

These active compounds may also be administered parenterally orintraperitoneally. Solutions or suspensions of these active compounds asa free base or pharmacologically acceptable salt can be prepared inwater suitably mixed with a surfactant such as hydroxypropylcellulose.Dispersions can also be prepared in glycerol, liquid polyethyleneglycols and mixtures thereof in oils. Under ordinary conditions ofstorage and use, these preparations contain a preservative to preventthe growth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases, the form must be sterile and must be fluid tothe extent that easy syringability exists. It must be stable under theconditions of manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol, polyol (e.g., glycerol, propylene glycol and liquidpolyethylene glycol), suitable mixtures thereof, and vegetable oils.

What is claimed is:
 1. A quinazolinone compound having the formula: ##STR30## wherein: R is ##STR31## --CO₂ H or --NHSO₂ CF₃ ; X is lower alkyl of 3 to 5 carbon atoms;R⁶ is: ##STR32## R¹ is H, lower alkyl of 1 to 4 carbon atoms (optionally substituted with --OR⁷, --CO₂ R⁷, --CN, --N(R⁷)(R¹³), phenyl, substituted phenyl (substitution selected from mono-lower alkyl of 1 to 3 carbon atoms, trifluoromethyl, nitro, O-alkyl of 1 to 3 carbon atoms, F, Cl, or Br)), phenyl, substituted phenyl (substitution selected from mono-lower alkyl of 1 to 3 carbon atoms, trifluoromethyl, nitro, O-alkyl of 1 to 3 carbon atoms, F, Cl, or Br), pyridinyl, thienyl, furyl --OR⁷, --CO₂ R⁷, --CN, --CON(R⁷)(R¹³), --CF₃, --SPh, --N(R⁷)(R¹³), or ##STR33## R² is H, lower alkyl of 1 to 4 carbon atoms (optionally substituted with --OR⁷, --CO₂ R⁷, --CN, --N(R⁷)(R¹³), phenyl, substituted phenyl (substitution selected from mono-lower alkyl of 1 to 3 carbon atoms, trifluoromethyl, nitro, O-alkyl of 1 to 3 carbon atoms, F, Cl, or Br)), phenyl, substituted phenyl (substitution selected from mono-lower alkyl of 1 to 3 carbon atoms, trifluoromethyl, nitro, O-alkyl of 1 to 3 carbon atoms, F, Cl, or Br), pyridinyl, thienyl, furyl --CO₂ R⁷, --CN, --CON(R⁷)(R¹³), or ##STR34## R³ is H, lower alkyl of 1 to 4 carbon atoms, phenyls substituted phenyl (substitution selected from mono-lower alkyl of 1 to 3 carbon atoms, trifluoromethyl, nitro, O-alkyl of 1 to 3 carbon atoms, F, Cl, or Br), pyridinyl, theinyl, furyl, --CO₂ R⁷, --CON(R⁷)(R¹³), --CN, --NO₂, or ##STR35## R⁴ is H, --CO₂ R⁷, --SO₂ R¹², lower alkyl of 1 to 4 carbon atoms, benzyl, substituted benzyl (substitution selected from mono-lower alkyl of 1 to 3 carbon atoms, trifluoromethyl, nitro, O-alkyl of 1 to 3 carbon atoms, F, Cl, or Br), phenyl, substituted phenyl (substitution selected from mono-lower alkyl of 1 to 3 carbon atoms, trifluoromethyl, nitro, O-alkyl of 1 to 3 carbon atoms, F, Cl, or Br), --CON(R⁷)(R¹³) or ##STR36## R¹² is phenyl, substituted phenyl (substitution selected from mono-lower alkyl of 1 to 3 carbon atoms, trifluoromethyl, nitro, O-alkyl of 1 to 3 carbon atoms, F, Cl, or Br); R⁵ is H, lower alkyl of 1 to 4 carbon atoms; R⁷ is H, lower alkyl of 1 to 4 carbon atoms; R⁸ is H, lower alkyl of 1 to 4 carbon atoms, phenyl, substituted phenyl (substitution selected from mono-lower alkyl of 1 to 3 carbon atoms, trifluoromethyl, nitro, O-alkyl of 1 to 3 carbon atoms, F, Cl, or Br), --CO₂ R⁷ , --CH₂ OH, --CN, --CON(R⁷)(R¹³) or ##STR37## R⁹ is H, lower alkyl of 1 to 4 carbon atoms, phenyl, substituted phenyl (substitution selected from mono-lower alkyl of 1 to 3 carbon atoms, trifluoromethyl, nitro, O-alkyl of 1 to 3 carbon atoms, F, Cl, or Br); R¹⁰ is H, lower alkyl of 1 to 4 carbon atoms (optionally substituted with --OR⁷, --CO₂ R⁷, --CN, --N(R⁷)(R¹³), phenyl, substituted phenyl (substitution selected from mono-lower alkyl of 1 to 3 carbon atoms, trifluoromethyl, nitro, O-alkyl of 1 to 3 carbon atoms, F, Cl, or Br)), phenyl, substituted phenyl (substitution selected from mono-lower alkyl of 1 to 3 carbon atoms, trifluoromethyl, nitro, O-alkyl of 1 to 3 carbon atoms, F, Cl, or Br), pyridinyl, theinyl, furyl, --OR⁷, --CO₂ R⁷, --CN, --CON(R⁷)(R¹³), --CF₃, or ##STR38## R¹³ is H, lower alkyl of 1 to 4 carbon atoms; Q is --O--, --(CR¹¹ R¹⁴)_(n) -- or a single bond; Q¹ is --O--, --(CR¹¹ R¹⁴)_(n) --, ##STR39## or a single bond; n is 1; A is --(CR¹¹ R¹⁴)_(m) --; m is 2; R¹¹ is H, lower alkyl to 1 to 4 carbon atoms (optionally substituted with --OR⁷, --CO₂ R⁷, --CN, --N(R⁷)(R¹³), phenyl, substituted phenyl (substitution selected from mono-lower alkyl of I to 3 carbon atoms, trifluoromethyl, nitro, O-alkyl of 1 to 3 carbon atoms, F, Cl, or Br)), phenyl, substituted phenyl (substitution selected from mono-lower alkyl of 1 to 3 carbon atoms, trifluoromethyl, nitro, O-alkyl of 1 to 3 carbon atoms, F, Cl, or Br) pyridinyl, thienyl, furyl, --OR⁷, --CO₂ R⁷, --CN, --CON(R⁷)(R¹³), --CF₃, or ##STR40## R¹⁴ is H, lower alkyl of 1 to 4 carbon atoms (optionally substituted with --OR⁷, --CO₂ R⁷, --CN, --N(R⁷)(R¹³), phenyl, substituted phenyl (substitution selected from mono-lower alkyl of 1 to 3 carbon atoms, trifluoromethyl, nitro, O-alkyl of I to 3 carbon atoms, F, Cl, or Br)), phenyl, substituted phenyl (substitution selected from mono-lower alkyl of 1 to 3 carbon atoms, trifluoromethyl, nitro, O-alkyl of 1 to 3 carbon atoms, F, Cl, or Br), pyridinyl, thienyl, furyl, --OR⁷, --CO₂ R⁷, --CN, --CON(R⁷)(R¹³), --CF₃, or ##STR41## or the pharmaceutically acceptable salts thereof.
 2. The compound according to claim 1 wherein said salts are selected from potassium, sodium, calcium, magnesium or ammonium.
 3. The compound according to claim 1 whereinX is a straight chain alkyl of 3 or 4 carbon atoms; R⁶ is ##STR42##
 4. The compound according to claim 1 wherein X is a straight chain alkyl of 3 or 4 carbon atoms;R⁶ is ##STR43##
 5. The compound according to claim 1 CIS-(+/-)-2-butyl-6-[1-(hydroxy-2-(2-pyrrolidinyl)ethyl]-3-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone.
 6. The compound according to claim 1 CIS-2-butyl-6-[1-hydroxy-1-methyl-2-(2-pyrrolidinyl)ethyl]-3-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl)methyl]-4(3H)-quinazolinone.
 7. The compound according to claim 1 trans-2-butyl-6-[1-hydroxy-1-methyl-2-(2-pyrrolidinyl)ethyl]-3-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone.
 8. The compound according to claim 1 2-butyl-6-[1-hydroxy-2-(2-piperidinyl)ethyl]-3-[[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone.
 9. The compound according to claim 1 2-butyl-6-[2-(5,5-dimethyl-2-pyrrolidinyl)-1-hydroxy-ethyl]-3-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone.
 10. The compound according to claim 1 ethyl 2-butyl-3,4-dihydro-(3-hydroxy-4-oxo-2-pyrrolidinyl) -3-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinepropionate.
 11. The compound according to claim 1 2-butyl-6-[l-hydroxy-2-(1,2,3,4-tetrahydro-1-isoquinolinyl)ethyl]-3-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]-methyl]-4(3H)-quinazolinone.
 12. The compound according to claim 1, 2-butyl-6-[1-hydroxy-1-methyl-2-(1,2,3,4-tetrahydro-1-isoquinolinyl)ethyl]-3-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]-methyl]-4(3H)-quinazolinone
 13. The compound according to claim 1, 2-butyl-6-[1-hydroxy-2-(2-methyl-2-piperidinyl)ethyl]-3-[[2'-(1H-tetrazol-5yl)[1,1'-biphenyl]-4-yl]-methyl]-4(3H)-quinazolinone.
 14. The compound according to claim 1, 2-butyl-6-[2-(5,5-dimethyl-2-pyrrolidinyl)-1-hydroxy-1-methylethyl]-3-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]-methyl]-4(3H)-quinazolinone.
 15. The compound according to claim 1, 2-butyl-6-[1-hydroxy-1-methyl-2-(2-piperidinyl)ethyl]-3-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]-methyl]-4(3H)-quinazolinone.
 16. The compound according to claim 1, 2-butyl-6-[2-(5,5-dimethyl-2-pyrrolidinyl)-1-hydroxy-1-methylethyl]-3-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]-methyl]-4(3H)-quinazolinone.
 17. The compound according to claim 1, 2-butyl-6-[1-hydroxy-1-phenyl-2-(2-pyrrolidinyl)ethyl]-3-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]-methyl]-4(3H)-quinazolinone.
 18. The compound according to claim 1, 2-butyl-6-[1-hydroxy-1-(2-pyrrolidinylmethyl)propyl]-3-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]-methyl]-4(3H)-quinazolinone.
 19. A pharmaceutical composition useful for treating angiotensin induced hypertension or congestive heart failure in a mammal comprising a suitable pharmaceutical carrier and an effective amount of a compound of claim
 1. 20. A method of treating angiotensin induced hypertension in a mammal comprising administering a compound of claim 1 to said mammal an amount effective to lower angiotensin induced hypertension.
 21. A method of treating congestive heart failure in a mammal comprising administering a compound of claim 1 to said mammal in an amount effective to treat congestive heart failure.
 22. A method of antagonizing the effects of Angiotensin II in a mammal comprising administering a compound of claim 1 to said mammal in an amount effective to treat the effects of Angiotensin II. 